The ASAM Principles of Addiction Medicine (6th Edition) (2018)

The
ASAM Principles of
Addiction Medicine
S I X T H E D I T I O N
The ASAM Principles of
Addiction Medicine
S I X T H E D I T I O N
Senior Editor
Shannon C. Miller, MD, DFAPA, DFASAM
Director, Addiction Services
VA Medical Center, Cincinnati, Ohio
Faculty, Neuroscience Graduate Program
Professor of Clinical Psychiatry, Affiliated, University of Cincinnati College of
Medicine
Past Founding Co-Editor, Journal of Addiction Medicine (2006-2016), American
Society of Addiction Medicine
Lieutenant Colonel, United States Air Force, Retired
Associate Editors
David A. Fiellin, MD, FASAM
Professor of Medicine, Emergency Medicine and Public Health
Director, Program in Addiction Medicine
Yale School of Medicine
New Haven, Connecticut
Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP,

FASAM
Professor of Psychiatry
Director of Addiction Psychiatry
Department of Psychiatry
Stony Brook University Medical Center
Stony Brook, New York
Richard Saitz, MD, MPH, FACP, DFASAM
Chairman, Department of Community Health Sciences (CHS)
Professor of Community Health Sciences & Medicine
Boston University Schools of Public Health and Medicine
Clinical Addiction Research and Education (CARE) Unit
Section of General Internal Medicine
Boston Medical Center
Boston, Massachusetts
Acquisitions Editor: Chris Teja
Product Development Editor: Ariel S. Winter
Editorial Coordinator: Ashley Pheiffer
Marketing Manager: Rachel Mante Leung
Production Project Manager: David Saltzberg
Design Coordinator: Stephen Druding
Manufacturing Coordinator: Beth Welsh
Prepress Vendor: SPi Global
Copyright © 2019 by (ASAM)
Fifth Edition, © 2014 by (ASAM)

Fourth Edition, © 2009 by (ASAM)
Third Edition, © 2003 by (ASAM)
Second Edition, © 1998 by (ASAM)
First Edition, © 1994 by (ASAM)
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Library of Congress Cataloging-in-Publication Data

Names: Miller, Shannon C., editor. | Fiellin, David A., editor. | Rosenthal, Richard N., editor. | Saitz,
Richard, editor. | American Society of Addiction Medicine, issuing body.
Title: The ASAM principles of addiction medicine / senior editor, Shannon C. Miller; associate editors,
David A. Fiellin, Richard N. Rosenthal, and Richard Saitz.
Other titles: Principles of addiction medicine (American Society of Addiction Medicine) | Principles of
addiction medicine
Description: Sixth edition. | Philadelphia : Wolters Kluwer, [2019] | Includes bibliographical references.
Identifiers: LCCN 2018038924 | ISBN 9781496370983
Subjects: | MESH: Substance-Related Disorders—therapy | Substance-Related Disorders—diagnosis |
Substance-Related Disorders—complications | Behavior, Addictive | Addiction Medicine
Classification: LCC RC564 | NLM WM 270 | DDC 362.29—dc23 LC record available at
https://lccn.loc.gov/2018038924
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Dedicated to all people whose lives have been affected by
addiction and related conditions and to those who care for
them based on respect and the best science available.
Section Editors
Peter Banys, MD, MSc

Clinical Professor of Psychiatry
University of California at San Francisco (UCSF)
San Francisco, California
Technical Expert, Addiction Treatment
WHO and European Union EPOS
Manila, Philippines
William C. Becker, MD
Associate Professor of Medicine (General Internal Medicine)
Yale University School of Medicine
Co-Director, Opioid Reassessment Clinic
VA Connecticut Healthcare System
West Haven, Connecticut
J. Wesley Boyd, MD, PhD

Associate Professor of Psychiatry and Faculty, Center for Bioethics
Harvard Medical School
Staff Psychiatrist
Cambridge Health Alliance
Cambridge, Massachusetts
Timothy K. Brennan, MD, MPH

Assistant Professor in Psychiatry
Director, Addiction Institute at Mt. Sinai West &
St. Luke’s
Director, Fellowship in Addiction Medicine Program
Icahn School of Medicine at Mount Sinai
New York, New York
Martin D. Cheatle, PhD

Associate Professor, Department of Psychiatry
Perelman School of Medicine
University of Pennsylvania
Director, Pain and Chemical Dependency Program
Center for Studies of Addiction
Philadelphia, Pennsylvania
Wilson M. Compton, MD, MPE

Deputy Director
National Institute on Drug Abuse
National Institutes of Health
U.S. Department of Health and Human Services
Bethesda, Maryland
John A. Dani, PhD

David J. Mahoney Professor of Neuroscience
Chair, Department of Neuroscience
Director, Mahoney Institute for Neuroscience
Lori J. Ducharme, PhD

Program Director for Health Services Research
National Institute on Alcohol Abuse and Alcoholism
Bethesda, Maryland
Robert L. DuPont, MD
President, Institute for Behavior and Health, Inc.
Rockville, Maryland
Georgetown University School of Medicine
Washington, District of Columbia
Rollin M. Gallagher, MD, MPH

Clinical Professor of Psychiatry and Anesthesiology
Director for Pain Policy Research and Primary Care
R. Jeffrey Goldsmith, MD
Professor of Clinical Psychiatry
Department of Psychiatry and Clinical Neuroscience
University of Cincinnati College of Medicine
Staff Psychiatrist
Mental Health Care Line
Cincinnati VA Medical Center
Cincinnati, Ohio
Adam Joseph Gordon, MD, MPH, FACP, DFASAM, CMRO

Elbert F. and Marie Christensen Endowed Research Professorship
Professor of Medicine and Psychiatry
University of Utah School of Medicine
Section Chief, Addiction Medicine
Salt Lake City VA Health Care System
Salt Lake City, Utah
David A. Gorelick, MD, PhD, DLFAPA

University of Maryland School of Medicine
Baltimore, Maryland
Jon E. Grant, MD, JD, MPH

Professor
Department of Psychiatry & Behavioral Neuroscience
Pritzker School of Medicine
University of Chicago
Chicago, Illinois
John R. Knight Jr, MD

Associate Professor of Pediatrics
Director, Center for Adolescent Substance Abuse Research
Division of Developmental Medicine
Boston Children’s Hospital
Thomas R. Kosten, MD
Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology,
Immunology & Pathology
Director, Dan Duncan Institute for Clinical and Translational Research
Baylor College of Medicine, Michael E. DeBakey VAMC
Houston, Texas
Kevin Kunz, MD, MPH, DFASAM

Executive Vice President
The Addiction Medicine Foundation
Chevy Chase, Maryland
Patrick G. O’Connor, MD, MPH

Dan Adams and Amanda Adams Professor of General Medicine
Chief, Section of General Internal Medicine
Department of Internal Medicine
Theodore V. Parran Jr, MD, FACP, FASAM

Isabel and Carter Wang Professor and Chair in Medical Education
CWRU School of Medicine
Co-Medical Director, Rosary Hall
St. Vincent Charity Medical Center
Cleveland, Ohio
Richard K. Ries, MD, FASAM, FAPA

Director Addictions Division
Department of Psychiatry and Behavioral Sciences
University of Washington School of Medicine
Seattle, Washington
Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP, FASAM

Seddon R. Savage, MD, MS, DFASAM

Adjunct Associate Professor of Anesthesiology
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire
Andrew J. Saxon, MD
Professor and Director
Addiction Psychiatry Residency Program
Department of Psychiatry & Behavioral Sciences
University of Washington
Director, Center of Excellence in Substance Abuse Treatment and Education
(CESATE)
Seattle, Washington
Corinne L. Shea, MA
Director of Programs and Communications
Institute for Behavior and Health, Inc.
Rockville, Maryland
Daryl Shorter, MD
Director of Residency Education
Assistant Professor
Menninger Department of Psychiatry and Behavioral Sciences
Staff Psychiatrist
Michael E. DeBakey VA Medical Center
Houston, Texas
Deborah R. Simkin, MD
Adjunct Assistant Professor
Emory School of Medicine
Atlanta, Georgia
Jeanette M. Tetrault, MD, FACP

Associate Professor of Medicine
Bonnie B. Wilford, MS
Coalition on Physician Education in Substance Use Disorders (COPE)
Easton, Maryland
Christine Yuodelis-Flores, MD, FAPA, FASAM

Associate Professor
Harborview Medical Center
Seattle, Washington
Joan E. Zweben, PhD

Health Sciences Clinical Professor of Psychiatry
University of California, San Francisco
Staff Psychologist
VA Medical Center
Contributors
Muhammad A. Abbas, MD
Clinical Assistant Professor
Department of Psychiatry and Human Behavior
Jersey Shore University Medical Center
Neptune City, New Jersey
Rutgers-Robert Wood Johnson Medical Center
Hackensack Meridian School of Medicine
New Brunswick, New Jersey
Kathleen M. Akgün, MD, MS

Assistant Professor of Medicine
Pulmonary, Critical Care and Sleep Medicine Section
Hospice and Palliative Medicine
Director
Medical Intensive Care Unit
Daniel P. Alford, MD, MPH

Professor of Medicine
Director, Clinical Addiction Research and Education (CARE) Unit
Boston University School of Medicine
Jeffrey Allgaier, MD, FACEP

Ideal Option Addiction Medicine Practice
Kennewick, Washington
Catreena Al Marj, MD
Post-Doctoral Fellow
University of Utah
Laith Al-Rabadi, MD
Assistant Professor of Nephrology
University of Utah Hospital
Hamada Hamid Altalib, DO, MPH

Director Yale Epilepsy Outcomes Research
Co-Director, Epilepsy Center of Excellence
Connecticut VA Healthcare System
Assistant Professor
Departments of Neurology & Psychiatry
Christopher A. Arger, PhD

Postdoctoral Fellow
Vermont Center on Behavior and Health
University of Vermont
Burlington, Vermont
Ashraf Attalla, MD
Associate Professor of Psychiatry
Emory University School of Medicine
Atlanta, Georgia
Program Director
Youth Services at Ridgeview Institute
Smyrna, Georgia
Reham A. Attia, MD, ABFM, ABAM

Core Faculty
Eisenhower Family Medicine Residency
Assistant Professor
University of California Riverside, School of Medicine
Rancho Mirage, California
Sanford Auerbach, MD
Associate Professor of Neurology, Psychiatry and Behavioral Neurosciences
Director
Sleep Disorders Center
Sudie E. Back, PhD

Professor of Psychiatry and Behavioral Sciences
Medical University of South Carolina
Director
DART Residency Research Track
Charleston, South Carolina
Robert L. Balster, PhD

Butler Professor of Pharmacology and Toxicology
Research Professor of Psychology and Psychiatry
Virginia Commonwealth University
Richmond, Virginia
Emma Louise Barrett, PhD

Fulbright Scholar, Psychiatry and Behavioral Sciences
Research Fellow, National Drug, Alcohol Research Centre
University of New South Wales
Sydney, Australia
Declan T. Barry, PhD

Director of Pain Treatment Services, APT Foundation
Director of Research, APT Foundation
Kristen L. Barry, PhD

Research Professor Emerita
Addiction Section
University of Michigan
Ann Arbor, Michigan
Andrea G. Barthwell, MD, DFASAM

Clinical Professor
State University of New York Stony Brook (SUNY) School of Social Welfare
Director and Founder, Two Dreams
Steven L. Batki, MD
Professor, Department of Psychiatry
UCSF School of Medicine
Chief, Addiction Recovery Treatment Services (ARTS), SFVAHCS
Director, Addiction Research Program UCSF/SFVAHCS
San Francisco Veterans Affairs Health Care System (SFVAHCS)
Michael H. Baumann, PhD

Staff Scientist and Facility Head
Designer Drug Research Unit, Intramural Research Program
National Institute on Drug Abuse, National Institutes of Health
Baltimore, Maryland
Louis E. Baxter Sr, MD, DFASAM

President and CEO
Professional Assistance Program of NJ, Inc.
Princeton, New Jersey
Assistant Clinical Professor of Medicine
Rutgers New Jersey Medical School
Newark, New Jersey
Co-Program Director
Howard University Addiction Medicine Fellowship
William C. Becker, MD
Associate Professor of Medicine (General Internal Medicine)
Co-Director, Opioid Reassessment Clinic
Neal L. Benowitz, MD
Professor of Medicine, Bioengineering and Therapeutic Sciences
University of California San Francisco
Nicolas Bertholet, MD, MSc

Associate Physician
Private Docent, Senior Lecturer
Alcohol Treatment Center
Department of Community Medicine and Health
Lausanne University Hospital
Lausanne, Switzerland
Roger L. Bertholf, PhD

Medical Director of Clinical Chemistry
Houston Methodist Hospital
Houston, Texas
Thomas J.R. Beveridge, MSc, PhD

Director, Medical Affairs—Oncology
Ipsen Biopharmaceuticals, Inc.
Basking Ridge, New Jersey
Assistant Professor (Adjunct)
Department of Physiology and Pharmacology
Wake Forest School of Medicine
Winston-Salem, North Carolina
Joyce N. Bittinger, PhD

Seattle, Washington
Richard D. Blondell, MD
Professor of Family Medicine
Department of Family Medicine, University at Buffalo
Director, DART Methadone Maintenance Clinic
Buffalo, New York
Erika Litvin Bloom, PhD

Assistant Professor (Research)
Departments of Psychiatry and Human Behavior and Medicine
Alpert Medical School of Brown University
Division of General Internal Medicine—Research
Rhode Island Hospital
Providence, Rhode Island
Frederic C. Blow, PhD

Senior Research Investigator
HSR&D Center for Clinical Management Research
Ann Arbor VA Healthcare System
UM Addiction Center
Ann Arbor, Michigan
Michael P. Bogenschutz, MD
New York University School of Medicine
New York, New York
Mark Bondeson, PsyD

Chief of Mental Health and Homeless Operations
Department of Veterans AffairsVeterans Integrated Service Network 20 (VISN
20)
Northwest Network, VA Healthcare System
Acting, Associate Chief of Staff for Behavioral Health
Department of Veterans Affairs
Boise, Veterans Administration Medical Center
Boise, Idaho
Jacob T. Borodovsky, BA
PhD Candidate, Center for Technology and Behavioral Health & The Dartmouth
Institute for Health Policy and Clinical Practice
Dartmouth Geisel School of Medicine
Lebanon, New Hampshire
Gilbert J. Botvin, PhD

Professor Emeritus
Department of Healthcare Policy and Research
Weill Cornell Medical College
New York, New York
Andria M. Botzet, MA, LAMFT

University of Minnesota
Minneapolis, Minnesota
Project Coordinator
Center for Adolescent Substance Abuse Research
J. Wesley Boyd, MD, PhD

Associate Professor of Psychiatry and Faculty,
Center for Bioethics
Staff Psychiatrist
Cambridge Health Alliance
Cambridge, Massachusetts
Maureen P. Boyle, PhD

Chief, Science Policy Branch
Bethesda, Maryland
Katharine A. Bradley, MD, MPH

Senior Scientific Investigator
Kaiser Permanente Washington Health Research Institute
Kaiser Permanente Washington
Associate Investigator
Health Services Research and Development
VA Puget Sound
Affiliate Professor
Department of Medicine
Department of Health Services
Seattle, Washington
Kathleen T. Brady, MD, PhD

Distinguished University Professor
Vice-President for Research
Clinical and Translational Science
Department of Psychiatry and Behavioral Science
Robert M. Bray, PhD

Chief Scientist, Behavioral Health/Criminal Justice Division
RTI International
Research Triangle Park, North Carolina
Timothy K. Brennan, MD, MPH
Assistant Professor in Psychiatry
Director, Addiction Institute at Mt. Sinai West & St. Luke’s
Director, Fellowship in Addiction Medicine Program
New York, New York
Traci L. Brooks, MD
Instructor in Pediatrics
Medical Director
School Based Health Centers, Cambridge Health Alliance
Staff Physician
Division of Adolescent/Young Adult Medicine
Lawrence S. Brown Jr, MD, MPH, DFASAM

Chief Executive Officer
START Treatment & Recovery Centers
Brooklyn, New York
Associate Physician
The Rockefeller University Hospital
Clinical Associate Professor of Medicine and Clinical Associate of Healthcare
Policy and Research
Department of Medicine, Weill Cornell Medical College
New York, New York
Richard A. Brown, PhD

Research Professor
School of Nursing
University of Texas at Austin
Austin, Texas
Gregory C. Bunt, MD
Assistant Professor Addiction Psychiatry
NYU School of Medicine
New York, New York
Randy L. Calisoff, MD
Assistant Professor of Physical Medicine and Rehabilitation
Northwestern University Feinberg School of Medicine
Attending Physician
Rehabilitation Institute of Chicago
Center for Pain Management
Chicago, Illinois
Deepa Camenga, MD, MHS

Assistant Professor of Emergency Medicine and Pediatrics
James W. Campbell, MD, MS

Professor of Family Medicine
CASE Western Reserve University
Chairman of Geriatrics
MetroHealth Medical Center
Cleveland, Ohio
Kathleen M. Carroll, PhD

Albert E. Kent Professor of Psychiatry
Director, Psychosocial Research, Division of Addictions
Principal Investigator, Psychotherapy Development Center for Drug Abuse
Jonathan P. Caulkins, PhD

University Professor of Operations Research and Public Policy
Carnegie Mellon University Heinz College
Pittsburgh, Pennsylvania
Martin D. Cheatle, PhD

Director, Pain and Chemical Dependency Program
Center for Studies of Addiction
H. Westley Clark, MD, JD, MPH

Dean’s Executive Professor of Public Health
Santa Clara University
Santa Clara, California
Jeffrey S. Cluver, MD
Associate Professor of Psychiatry & Behavioral Sciences
Deputy Chair & Vice Chair for Education & Training
John J. Coleman
Assistant Administrator (Ret.)
Drug Enforcement Administration
Peggy Compton, RN, PhD, FAAN

Associate Professor of Nursing
University of Pennsylvania School of Nursing
Wilson M. Compton, MD, MPE

Deputy Director
Bethesda, Maryland
David J. Copenhaver, MD, MPH
Associate Professor
Director of Cancer Pain Management
Director of Pain Telehealth Programs
Senior Editor Anesthesia & Analgesia
Division of Pain Medicine
Anesthesiology and Pain Medicine
University of California at David
Sacramento, California
Megan E. Crants
Medical Student
Touro College of Osteopathic Medicine
Middletown, New York
Stanley D. Crittenden, MD
Lead Medical Director
Humana, Inc.
Louisville, Kentucky
Rosa M. Crum, MD, MHS

Professor, Department of Epidemiology,
Joint Appointment, Department of Psychiatry & Behavioral Sciences
Johns Hopkins Medical Institutions
Baltimore, Maryland
Dennis C. Daley, PhD, LSW

Senior Director, Substance Use Services, Behavioral Health Integration Division
UPMC Insurance Division
Department of Psychiatry, University of Pittsburgh
School of Medicine
Kalyan Dandala, MD
Chief Medical Officer
Associated Behavioral Health Care
Clinical Associate Professor
Seattle Pacific University
Seattle University
Seattle, Washington
John A. Dani, PhD

David J. Mahoney Professor of Neuroscience
Chair, Department of Neuroscience
Director, Mahoney Institute for Neuroscience
Itai Danovitch, MD, MBA

Chairman, Department of Psychiatry and Behavioral Neurosciences
Associate Clinical Professor of Psychiatry
Cedars-Sinai Medical Center
Los Angeles, California
Danielle R. Davis, MA
Predoctoral Fellow
Vermont Center on Behavior & Health
Burlington, Vermont
George De Leon, PhD

Science Director
Behavioral Science Training
School of Nursing
New York University
New York, New York
Christina M. Delos Reyes, MD
Director, Addiction Psychiatry Fellowship
University Hospitals Cleveland Medical Center
Cleveland, Ohio
Adam R. Demner, MD
Clinical Assistant Professor of Psychiatry
Unit Chief, Chemical Dependency Outpatient Program
Bellevue Hospital Center
New York, New York
Helen Dermatis, PhD

Research Associate Professor of Psychiatry
Division of Alcoholism and Drug Abuse
New York, New York
Monica M. Diaz, MD
Neuroinfectious & Neuroimmunology Fellow
University of California, San Diego Health
San Diego, California
William E. Dickinson, DO, FAAFP, ABAM, DFASAM

Medical Director
Providence Alcohol and Drug Treatment Services
Everett, Washington
Patricia Jean Dickmann, MD

Assistant Professor of Psychiatry
University of Minnesota Medical School
Medical Director, Addiction Recovery Services
Medical Director, Opioid Treatment Program
Medical Director, Community Resource and Referral Center
Minneapolis VA Medical Center
Edward F. Domino, MS, MD

Active Emeritus
Department of Pharmacology
The University of Michigan Medical School
Ann Arbor, Michigan
Gail D’Onofrio, MD, MS

Professor and Chair
Department of Emergency Medicine
Physician-in-Chief
Emergency Department
Yale-New Haven Hospital
Dennis M. Donovan, PhD

Director, Alcohol & Drug Abuse Institute
Professor, Psychiatry & Behavioral Sciences
Adjunct Professor, Psychology, Health Services, and Global Health
University of Washington Schools of Medicine and Public Health
Seattle, Washington
Antoine Douaihy, MD
Professor of Psychiatry & Medicine
University of Pittsburgh School of Medicine
Senior Academic Director of Addiction Medicine Services
Director of Addiction Psychiatry Fellowship
Western Psychiatric Institute and Clinic
Co-Director of Tobacco Treatment Service
University of Pittsburgh Medical Center
Robert L. DuPont, MD
President, Institute for Behavior and Health, Inc.
Rockville, Maryland
Georgetown University School of Medicine
Paul H. Earley, MD, DFASAM

Medical Director
Georgia Professionals Health Program
Atlanta, Georgia
Jon O. Ebbert, MD
Mayo Clinic
Rochester, Minnesota
Steven J. Eickelberg, MD, FAPA, DFASAM

President
Medical Education and Research Foundation for the Treatment of Addiction
(MERF)
A. Ahsan Ejaz, MD
Division of Nephrology, Hypertension and Renal Transplantation
University of Florida
Gainesville, Florida
Nady el-Guebaly, MD, DPsych, DPH, FRCPC, DABAM

Professor and Head, Division of Addiction
Department of Psychiatry, University of Calgary
Calgary, Alberta, Canada
Ralph L. Elkins
Private Practitioner
Augusta, Georgia
Xiaoduo Fan, MD, MPH, MSc
Director, Psychotic Disorders Program
Director, China Mental Health Program
UMass Memorial Health Care/UMass Medical School
Worcester, Massachusetts
James L. Ferguson, DO, DFASAM

Medical Director, Recovery Management Services
FirstSource Solutions
Chalfont, Pennsylvania
Sergi Ferré, MD, PhD

Senior Investigator, Integrative Neurobiology Section
National Institute on Drug Abuse, Intramural Research Program
National Institutes of Health, Department of Health and Human Services
Baltimore, Maryland
David A. Fiellin, MD, FASAM

Professor of Medicine, Emergency Medicine and Public Health
Director, Program in Addiction Medicine
James W. Finch, MD, DFASAM

Director of Physician Education
Governor’s Institute on Substance Abuse
Raleigh, North Carolina
Medical Director
Changes By Choice
Durham, North Carolina
Deborah S. Finnell, DNS, PMHNP-BC, CARN-AP, FAAN

Professor
Johns Hopkins University
Baltimore, Maryland
Marc Fishman, MD
Assistant Professor
Psychiatry
Johns Hopkins University School of Medicine
Medical Director
Maryland Treatment Centers
Baltimore, Maryland
Scott M. Fishman, MD
Charles & Patricia Fullerton Endowed Chair
Professor of Anesthesiology and Pain Medicine
Chief, Division of Pain Medicine
Vice Chair, Department of Anesthesiology and Pain Medicine
Director, Center for Advancing Pain Relief (CAPR)
UC David Medical Center
Michael F. Fleming, MD, MPH

Vice Chair for Faculty Development
Northwestern University
Professor of Psychiatry and Behavioral Sciences and Family and Community
Medicine
Associate Director
Northwestern University
Clinical and Translational Sciences Institute (NUCATS)
The Center for Education and Career Development
Chicago, Illinois
James H. Ford II, PhD, FHIMSS, FACHE

Associate Scientist
Center for Health Systems Research and Analysis
University of Wisconsin–Madison
Madison, Wisconsin
P. Joseph Frawley, MD
Internal Medicine/Addiction Medicine
Co-Medical Director, Recovery Road Medical
Center
Santa Barbara, California
Carl H. Freyer, BSc, MBBS

Advanced Trainee, Gastroenterology and Addiction
Medicine
Drug Health Services
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
Peter D. Friedmann, MD, MPH, FACP, DFASAM

Chief Research Officer, Baystate Health
Associate Dean for Research and Professor of Medicine
University of Massachusetts Medical School (UMMS)–
Baystate
Professor of Quantitative Health Sciences
UMMS
Springfield, Massachusetts
Marc Galanter, MD, FASAM

Research Professor of Psychiatry
New York, New York
Rollin M. Gallagher, MD, MPH

Clinical Professor of Psychiatry and Anesthesiology
Director for Pain Policy Research and Primary Care
Gilberto Gerra, MD
Chief, Drug Prevention and Health Branch
Division of Operations
United Nations Office on Drugs and Crime
Vienna, Austria
Amanda K. Gilmore, PhD

Assistant Professor (Research)
College of Nursing and Department of Psychiatry & Behavioral Sciences
Mark S. Gold, MD
17th Distinguished Alumni Professor
University of Florida
Adjunct Professor
Washington University in St. Louis School of Medicine
St. Louis, Missouri
Bruce A. Goldberger, PhD, F-ABFT

Chief, Director and Professor
Division of Forensic Medicine
Department of Pathology, Immunology and Laboratory Medicine
University of Florida College of Medicine
R. Jeffrey Goldsmith, MD
Professor of Clinical Psychiatry
Department of Psychiatry and Clinical Neuroscience
University of Cincinnati College of Medicine
Staff Psychiatrist
Mental Health Care Line
Cincinnati VA Medical Center
Cincinnati, Ohio
David A. Gorelick, MD, PhD, DLFAPA

University of Maryland School of Medicine
Baltimore, Maryland
Praveen Gounder, MBBS (Hons)

Clinical Pharmacology Advanced Trainee
Sydney, Australia
Brian Grahan, MD, PhD

Medical Director of Quality Measures
Director, Minnesota Opioid and Addictions Care Project ECHO
Hennepin Healthcare
Jon E. Grant, MD, JD, MPH

Professor
Department of Psychiatry & Behavioral Neuroscience
Pritzker School of Medicine
University of Chicago
Chicago, Illinoi
Kevin M. Gray, MD
Professor and Director, Child and Adolescent Psychiatry
Kenneth W. Griffin, PhD, MPH

Professor
Department of Healthcare Policy and Research
Weill Cornell Medical College
New York, New York
Roland R. Griffiths, PhD

Professor
Department of Psychiatry of Behavioral Sciences
Department of Neuroscience
Baltimore, Maryland
Daniel F. Gros, PhD

Associate Professor, Department of Psychiatry and Behavioral Sciences
Section Chief, Supervisory Psychologist, PCMHI/CBT programs
Principal Investigator, VA Clinical Sciences R&D
Mental Health Service 116, Ralph H. Johnson VAMC
Kathleen A. Gross, MD
Clinical Research Coordinator
Center for Clinical Research
Western Michigan University–Homer Stryker M.D. School of Medicine
Kalamazoo, Michigan
Joel W. Grube, PhD

Senior Research Scientist, Prevention Research Center, Pacific Institute for
Research and Evaluation
Oakland, California
Paul J. Gruenewald, PhD

Scientific Director, Senior Research Scientist
Prevention Research Center, Pacific Institute for Research and Evaluation
Oakland, California
Carolina L. Haass-Koffler, PHARMD

Assistant Professor
Center for Alcohol and Addiction Studies
Department of Psychiatry and Human Behavior
Department of Behavioral and Social Sciences
Brown University
Paul S. Haber, MD, FRACP, FAChAM
Professor
Drug Health Services
Camperdown, New South Wales, Australia
Timothy M. Hall, MD, PhD, FAPA, FASAM

Assistant Clinical Professor
Center for Behavioral & Addiction Medicine
Department of Family Medicine
David Geffen School of Medicine
University of California, Los Angeles
Deborah L. Haller, PhD

Voluntary Professor
Department of Public Health Sciences
University of Miami Miller Medical School
Miami, Florida
Chief Psychologist
NFL Program of Substances of Abuse
Colleen A. Hanlon, PhD

Brain Stimulation Division
Center for Biomedical Imaging
Departments of Psychiatry and Neurosciences
College of Medicine
Drew A. Harris, MD
Fellow, Pulmonary, Critical Care and Sleep Medicine
Sion Kim Harris, PhD, CPH

Assistant Professor of Pediatrics
Co-Director, Center for Adolescent Substance Abuse Research
Karen J. Hartwell, MD
Associate Professor of Psychiatry and Behavioral Sciences
Addiction Sciences Division
Medical Director
Substance Treatment and Recovery Program
Ralph H. Johnson VAMC
Kathryn Hawk, MD, MHS

Assistant Professor of Emergency Medicine
Nicole A. Hayes, MS
Doctoral Candidate, Psychiatry and Behavioral Sciences
Chicago, Illinois
J. Taylor Hays, MD
Mayo Clinic College of Medicine and Science
Director, Nicotine Dependence Center
Mayo Clinic
Jason J. Heavner, MD
Pulmonary & Critical Care Medicine
University of Maryland
Baltimore Washington Medical Center
Baltimore, Maryland
Sarah H. Heil, PhD

Associate Professor with Tenure
Vermont Center on Behavior and Health
Departments of Psychiatry and Psychological Science
Burlington, Vermont
Abigail J. Herron, DO, DFASAM, FAPA

Director of Psychiatry, Director of Fellowship in Addiction Medicine
The Institute for Family Health
Assistant Clinical Professor of Psychiatry and Family Medicine
Icahn School of Medicine at Mt. Sinai
New York, New York
Stephen T. Higgins, PhD

Director, Vermont Center on Behavior and Health
Virginia H. Donaldson Professor of Translational Science
Departments of Psychiatry and Psychological Science
Vice Chair, Department of Psychiatry
Burlington, Vermont
Kenneth Hoffman, MD, MPH

Colonel (retired)
Medical Corps
US Army
Kim A. Hoffman, PhD

Senior Research Associate
OHSU-PSU School of Public Health
Portland, Oregon
Matthew Owen Howard, PhD

Daniel Distinguished Professor
Associate Dean for Doctoral Education
School of Social Work
University of North Carolina
Chapel Hill, North Carolina
Mark Hrymoc, MD
Assistant Clinical Professor
Department of Psychiatry and Biobehavioral Sciences
Keith Humphreys, PhD

Stanford University School of Medicine
Stanford, California
Senior Research Career Scientist
Veterans Affairs Health Care System
Palo Alto, California
Richard D. Hurt, MD
Emeritus Professor of Medicine, College of Medicine
Emeritus Director, Nicotine Dependence Center
Mayo Clinic
Ryan T. Hurt, MD, PhD

Mayo Clinic
Gwendolyne Anyanate Jack, MD, MPH

Department of Endocrinology, Diabetes and Metabolism
Beth Israel Deaconess Medical Center
Jerome H. Jaffe, MD
Friends Research Institute
Baltimore, Maryland
Steven L. Jaffe, MD, DFAPA, LFACCAP

Professor Emeritus of Psychiatry
Emory University School of Medicine
Morehouse School of Medicine
Atlanta, Georgia
Clinical Director
The Insight Program
Roswell, Georgia
Julie K. Johnson, PhD

Postdoctoral Fellow
Department of Mental Health
Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
Kimberly Johnson, MBA, PhD

Associate Professor
Louis De La Parte Florida Mental Health Institute
Department of Mental Health Law and Policy
College of Behavioral and Community Sciences
Tampa, Florida
Christopher M. Jones, PharmD, MPH

Acting Associate Deputy Assistant Secretary (Science and Data Policy)
Office of the Assistant Secretary for Planning and Evaluation
Hendrée E. Jones, PhD

Executive Director, UNC Horizons
Professor, Department of Obstetrics and Gynecology
Carrboro, North Carolina
Laura M. Juliano, PhD

Professor
Department of Psychology
American University
Christopher W. Kahler, PhD

Professor of Behavioral and Social Sciences
Center for Alcohol and Addiction Studies
Brown University School of Public Health
David Kan, MD, DFASAM

Associate Clinical Professor
Medical Director, Bright Heart Health
San Ramon, California
Private Practice
Walnut Creek, California
Lori D. Karan, MD, FACP, DFASAM

Professor of Internal Medicine and Preventive Medicine
Loma Linda University School of Medicine &
VA Loma Linda Health Care System
Loma Linda, California
Jag H. Khalsa, MS, PhD

Chief, Medical Consequences Branch
Division of Therapeutics and Medical Consequences
Bethesda, Maryland
Therese K. Killeen, PhD, APRN, BC

Research Professor
Addictions Sciences Division
Beau Kilmer, PhD

Co-Director, RAND Drug Policy Research Center
RAND Corporation
Jason R. Kilmer, PhD

Associate Professor
Psychiatry & Behavioral Sciences, School of Medicine
Assistant Director of Health & Wellness for Alcohol & Other Drug Education
Health & Wellness, Division of Student Life
Seattle, Washington
Simeon D. Kimmel, MD, MA

Infectious Disease and Addiction Fellow
Drew D. Kiraly, MD, PhD

Assistant Professor, Psychiatry & Neuroscience
Attending Physician, Psychiatry
The Mount Sinai Hospital
New York, New York
Barbara M. Kirrane, MD, MPH

Medical Toxicology Consultant
Saint Barnabas Medical Center
Physician Advisor
Department of Case Management
Saint Barnabas Medical Center
Livingston, New Jersey
John R. Knight Jr, MD

Director, Center for Adolescent Substance Abuse
Research
Division of Developmental Medicine
Brian B. Koo, MD
Associate Professor of Neurology
Director, Sleep Laboratory
Connecticut Veterans Affairs Health Care Systems
George F. Koob, PhD

Director
National Institute on Alcohol Abuse and Alcoholism
Bethesda, Maryland
Thomas R. Kosten, MD
Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology,
Immunology & Pathology
Director, Dan Duncan Institute for Clinical and Translational Research
Baylor College of Medicine, Michael E. DeBakey VAMC
Houston, Texas
Walker H. Krepps
Graduate Student, Stem Cell Biology
University of Minnesota, Stem Cell Institute
Kevin Kunz, MD, MPH, DFASAM

Chevy Chase, Maryland
Matthew M. LaCasse, DO
Instructor, Department of Psychiatry
Kalamazoo, Michigan
Maritza E. Lagos, MD, DABAM

Associate Professor
Kalamazoo, Michigan
Cynthia L. Lancaster, PhD

Assistant Professor, Clinical Psychology
University of Nevada, Reno
Reno, Nevada
Mary E. Larimer, PhD

Professor of Psychiatry & Behavioral Sciences and Psychology
University of Washington University School of Medicine
Director, Center for the Study of Health & Risk Behaviors
Seattle, Washington
Celine Larkin, PhD

Postdoctoral Research Fellow, Department of Emergency Medicine
University of Massachusetts Medical School
David Y.W. Lee, PhD
Associate Professor
Harvard Medical School/McLean Hospital
Director
Bio-Organic & Natural Products Laboratory
McLean Hospital
Belmont, Massachusetts
Janet H. Lenard, EdD, LCSW, CCS, CAC II

Department of the Army Clinical Program Manager (retired)
Army Substance Abuse Program
Installation Management Headquarters Command
Fort Sam
Houston, Texas
Adam M. Leventhal, PhD

Associate Professor of Preventive Medicine and Psychology
University of Southern California, Keck School of Medicine
Director, Health, Emotion, and Addiction Laboratory
University of Southern California, Keck School of Medicine
Frances R. Levin, MD
Kennedy Leavy Professor of Psychiatry at CUMC
Columbia University Medical Center
New York, New York
Petros Levounis, MD, MA

Professor and Chair, Department of Psychiatry
Rutgers New Jersey Medical School
Chief of Service
University Hospital
Newark, New Jersey
Aron H. Lichtman, PhD

Professor of Pharmacology and Toxicology and Medicinal Chemistry
Associate Dean of Research and Graduate Studies, School of Pharmacy
Richmond, Virginia
Michael R. Liepman, MD, DFAPA, FASAM†

Professor, Psychiatry
Addiction Psychiatry Director
Department Director of Research
Western Michigan University School of Medicine
Kalamazoo, Michigan
Ty W. Lostutter, PhD
Assistant Professor
Center for the Study of Health & Risk Behaviors
Director, Psychology Internship Program
University of Washington’s School of Medicine
Seattle, Washington
Scott E. Lukas, PhD

Professor of Psychiatry (Pharmacology)
Director, McLean Imaging Center
Director, Behavioral Psychopharmacology Research Laboratory
McLean Hospital
Brian C. Mac Grory, MB, BCh, BAO, MRCP

Staff Neurologist, Rhode Island Hospital Comprehensive Stroke Center
Assistant Professor of Neurology
Warren Alpert Medical School at Brown University
Alan Ona Malabanan, MD, CCD, FACE
Program Director, Endocrinology Fellowship
Training Program
Beth Israel Deaconess Medical Center
Robert Malcolm, MD
Family Medicine and Pediatrics
Associate Dean for SME
Marianne T. Marcus, EdD, RN, FAAN

Professor Emerita
University of Texas Health Science Center School of Nursing
Houston, Texas
John J. Mariani, MD
Associate Professor of Clinical Psychiatry
Division on Substance Use Disorders
Director, Substance Treatment and Research Service
New York, New York
G. Alan Marlatt, PhD†

Professor of Psychology
Seattle, Washington
Lisa A. Marsch, PhD

Director, Center for Technology and Behavioral
Health
Professor, Department of Psychiatry
Dartmouth Geisel School of Medicine
Lebanon, New Hampshire
Suena H. Massey, MD
Associate Professor of Psychiatry & Behavioral Sciences and Medical Social
Sciences
Northwestern Memorial Hospital
Chicago, Illinois
Elinore F. McCance-Katz, MD, PhD

Professor of Psychiatry and Human Behavior
Alpert Medical School
Brown University
Chief Medical Officer
Rhode Island Department of Behavioral Healthcare
Developmental Disabilities and Hospitals
John J. McCarthy, MD
University of California Davis School of Medicine
Davis, California
Volunteer Clinical Faculty
Richard A. McCormick, PhD

Senior Scholar
Center for Healthcare Research and Policy
MetroHealth/Case Western Reserve University
Cleveland, Ohio
Barbara S. McCrady, PhD

Distinguished Professor of Psychology
Director, Center on Alcoholism, Substance Abuse and Addictions
University of New Mexico
Albuquerque, New Mexico
David D. McFadden, MD
Assistant Professor of Medicine, College of
Medicine
General Internal Medicine
Mayo Clinic
Mark McGovern, PhD

Professor, Department of Psychiatry & Behavioral Sciences and Department of
Medicine
Stanford University School of Medicine
Co-Chief, Division of Public Mental Health and
Population Sciences, Department of Psychiatry & Behavioral Sciences
Medical Director, Integrated Behavioral Health, Division of Primary Care and
Population Health
Stanford Health Care
Palo Alto, California
A. Thomas McLellan, PhD

Professor Emeritus
David Mee-Lee, MD, FASAM

President
DML Training and Consulting
Davis, California
Delinda E. Mercer, PhD, MSCP, MAC

Licensed Psychologist
Regional West Health Systems
Scottsbluff, Nevada
Contributing Faculty, School of Psychology
Walden University
Jessica S. Merlin, MD, PhD, MBA

Visiting Associate Professor of Medicine
Divisions of General Internal Medicine and Infectious Diseases
University of Pittsburgh School of Medicine
Lisa J. Merlo, PhD, MPE

University of Florida College of Medicine
Shannon C. Miller, MD, DFAPA, DFASAM

Director, Addiction Services
VA Medical Center, Cincinnati, Ohio
Faculty, Neuroscience Graduate Program
Professor of Clinical Psychiatry, Affiliated, University of Cincinnati College of
Medicine
Past Founding Co-Editor, Journal of Addiction Medicine (2006-2016), American
Society of Addiction Medicine
Lieutenant Colonel, United States Air Force, Retired
Margaret R. Moon, MD, MPH

Johns Hopkins University, School of Medicine
Chief Medical Officer, The Johns Hopkins Children’s Center
Core Faculty, The Johns Hopkins Berman Institute of Bioethics
Baltimore, Maryland
Hugh Myrick, MD
Acting Chief Mental Health Officer VISN 7
ACOS, Mental Health Service Lince
Director, Addiction Sciences Division
Director, Military Sciences Division
Edgar P. Nace, MD
University of Texas Southwestern Medical School
Dallas, Texas
Eric J. Nestler, MD, PhD

Nash Family Professor of Neuroscience
Director, Friedman Brain Institute
Dean for Academic and Scientific Affairs
New York, New York
David E. Nichols, PhD

Adjunct Professor of Chemical Biology and Medicinal Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Tatjana Novakovic-Agopian, PhD

Director Rehabilitation Neuropsychology
San Francisco VA Medical Center
University of California San Francisco School of Medicine
Edward V. Nunes, MD
Columbia University–New York State Psychiatric Institute
New York, New York
Patrick G. O’Connor, MD, MPH

Dan Adams and Amanda Adams Professor of General Medicine
Brian L. Odlaug, PhD, MPH

Visiting Researcher
Faculty of Health & Medical Sciences
University of Copenhagen
Adjunct Faculty
Science & Health Department
Danish Institute for Study Abroad (DIS)
Copenhagen, Denmark
Dennis E. Orwat, MD
Fellow, Addiction Psychiatry
Medicine University of South Carolina
James A.D. Otis, MD, FAAN

Director, Pain and Headache Group
Simy K. Parikh, MD
Jefferson Headache Center
Thomas Jefferson University
Theodore V. Parran Jr, MD, FACP, FASAM

Isabel and Carter Wang Professor and Chair in Medical Education
CWRU School of Medicine
Co-Medical Director, Rosary Hall
St. Vincent Charity Medical Center
Cleveland, Ohio
Mallie J. Paschall, PhD

Senior Research Scientist
Prevention Research Center, Pacific Institute for Research and Evaluation
Oakland, California
Huned S. Patwa, MD
Chief, Neurology Service
David L. Pennington, PhD

Assistant Professor, Department of Psychiatry
University of California San Francisco
Assistant Director, Addiction Research Program
San Francisco VA Medical Center
India Perez-Urbano, BA
Study Coordinator
Division of General and Internal Medicine
Albert Einstein College of Medicine
Bronx, New York
Founder and Executive Director
Rockland Connects, Inc.
Nyack, New York
Michael Perloff, MD, PhD

Assistant Professor
Neurology
Department of Neurology and the Pain Management Group
Boston University Medical Center
Steven Pfau, MD
Department of Medicine (Cardiology)
Karran A. Phillips, MD, MSc

Senior Clinician and Clinical Director
Baltimore, Maryland
Javier Ponce Terashima, MD

Adult Psychiatry Resident
University Hospitals Cleveland Medical Center–
Case Western Reserve University
Cleveland, Ohio
Adrian Popescu, MD
Assistant Professor of Clinical Physical Medicine and Rehabilitation
Department of Physical Medicine and Rehabilitation
Assistant Professor of Anesthesiology and Critical Care
Marc N. Potenza, MD, PhD

Professor of Psychiatry, Child Study and Neuroscience
Director, Center of Excellence on Gambling Research
Director, Women and Addictions Core, Women’s Health Research at Yale
Director, Impulsivity and Impulse Control Disorder Research Program
Vladimir Poznyak, MD, PhD

Coordinator, Management of Substance Abuse
Department of Mental Health and Substance Abuse
World Health Organization
Geneva, Switzerland
Wesley Prickett, MD
Pain Physician/Anesthesiologist
U.S. Department of Veterans Affairs
Nebraska-Western Iowa Healthcare System
Omaha, Nebraska
James O. Prochaska, PhD

Cancer Prevention Research Center
University of Rhode Island
Kingston, Rhode Island
Yelena Gorfinkel Pyatkevich, MD

Instructor of Neurology
Gary M. Reisfield, MD
University of Florida School of Medicine
Richard K. Ries, MD, FAPA, FASAM

Director Addictions Division
University of Washington School of Medicine
Seattle, Washington
Paul J. Rinaldi, PhD
Clinical Psychologist
Adjunct Assistant Professor of Psychiatry
Mount Sinai Icahn School of Medicine
New York, New York
David C.S. Roberts, PhD

Professor Emeritus, Department of Physiology and Pharmacology
Wake Forest School of Medicine
Winston-Salem, North Carolina
Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP, FASAM

Stephen Ross, MD
Associate Professor of Psychiatry & Child and Adolescent Psychiatry
NYU Langone Medical Center
Bellevue Hospital Center
Senior Consultant, Division of Alcoholism & Drug Abuse, Bellevue Hospital
Center
Senior Consultant, Division of Addiction Psychiatry, NYU Tisch Hospital
New York, New York
Stanley Sacks, PhD

Senior Research Scientist Emeritus
National Development and Research Institutes, Inc.
New York, New York
Michael E. Saladin, PhD

Professor
Department of Health Sciences and Research
College of Health Professions
Richard Saitz, MD, MPH, FACP, DFASAM

Chairman, Department of Community Health Sciences (CHS)
Professor of Community Health Sciences & Medicine
Boston University Schools of Public Health and Medicine
Clinical Addiction Research and Education (CARE) Unit
Section of General Internal Medicine
Robert F. Saltz, PhD

Senior Scientist
Prevention Research Center
Pacific Institute for Research & Evaluation
Berkeley, California
Jeffrey H. Samet, MD, MA, MPH

Vice Chair for Public Health, Department of Medicine
John Noble MD Professor of Medicine and
Professor of Community Health Sciences
Boston University Schools of Medicine and Public Health
Friedhelm Sandbrink, MD
Clinical Associate Professor in Neurology
Uniformed Services University
Bethesda, Maryland
Assistant Clinical Professor of Neurology
George Washington University
Director, Pain Management Program
Department of Neurology
Washington VA Medical Center
Christine L. Savage, PhD, RN, CARN, FAAN

Adjunct Professor
Johns Hopkins University School of Nursing
Baltimore, Maryland
Andrew J. Saxon, MD
Addiction Psychiatry Residency Program
Director, Center of Excellence in Substance Abuse
Treatment and Education (CESATE)
Seattle, Washington
Emmanuelle A.D. Schindler, MD, PhD

Veterans Affairs Special Fellow, Neurosciences
Veterans Affairs Connecticut Healthcare System
Clinical Instructor, Neurology
Simone H. Schriger, BA
Center for Behavioral & Addiction Medicine
Frank J. Schwebel, MS
Graduate Student, Department of Psychology
Seattle, Washington
Mark F. Seltzer Esq

Founder
Seltzer and Associates, P.C.
Samit Shah, MD, PhD

Clinical Fellow in Cardiovascular Disease
Steven Shoptaw, PhD

Vice Chair and Professor, Family Medicine
Professor, Psychiatry and Biobehavioral Sciences
David Geffen School of Medicine
Director, Center for Behavioral and Addiction
Medicine
Director, Center for HIV Identification, Prevention and Treatment Services
Daryl Shorter, MD
Director of Residency Education
Assistant Professor
Menninger Department of Psychiatry and Behavioral Sciences
Staff Psychiatrist
Michael E. DeBakey VA Medical Center
Houston, Texas
Gerald D. Shulman, MA, MAC, FACATA

Trainer & Consultant
Shulman & Associates Training and in Behavioral Health
Jacksonville, Florida
Jason J. Sico, MD, MHS, FAHA, FACP

Director, Stroke Care
Assistant Professor, Departments of Neurology and Internal Medicine (General
Medicine)
Deborah R. Simkin, MD
Adjunct Assistant Professor
Emory School of Medicine
Atlanta, Georgia
Girish Singhania, MBBS

Division of Nephrology & Hypertension
University of Utah
David Smelson, PsyD

Professor and Vice Chair
University of Massachusetts Medical School
Director, Translational Research
Bedford VA Medical Center
Bedford, Massachusetts
Tricia H. Smith, PhD

Faculty Instructor
Department of Biology
Richmond, Virginia
Ramon Solhkhah, MD
Founding Chairman, Department of Psychiatry & Behavioral Health
Professor of Psychiatry & Behavioral Health and Pediatrics
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Chairman, Department of Psychiatry
Jersey Shore University Medical Center
Neptune, New Jersey
Sharon Stancliff, MD, FAAFP, FASAM

Medical Director
Harm Reduction Coalition
New York, New York
Steven P. Stanos, DO
Pain Medicine Specialist & Physiatrist
Medical Director, Swedish Pain Services
Swedish Health System
President
American Academy of Pain Medicine
Seattle, Washington
Joanna L. Starrels, MD, MS

Albert Einstein College of Medicine and Montefiore Medical Center
Bronx, New York
Gideon St. Helen, PhD

Assistant Professor
Division of Clinical Pharmacology
Randy Stinchfield, PhD

University of Minnesota Medical School
Susan M. Stine, MD, PhD

Professor Emeritus
Department of Psychiatry and Behavioral Neurosciences
Wayne State University School of Medicine
Detroit, Michigan
Susan A. Storti, PhD, RN, NEA-BC, CARN-AP

Administrator of Health Homes and Mental Health Policy
Substance Use and Mental Health Leadership Council of RI
Warwick, Rhode Island
Geetha A. Subramaniam, MD, DFAPA, DFAACAP

Deputy Director
Center for Clinical Trials Network
Bethesda, Maryland
Carol A. Sulis, MD
Medical Director, Infection Control and Hospital
Epidemiology
Mary M. Sweeney, PhD

Baltimore, Maryland
Zebulon Charles Taintor, MD

Adjunct Professor of Psychiatry
New York, New York
Jenni Teeters, MS
Clinical Psychology Doctoral Candidate
University of Memphis
Memphis, Tennessee
Jeanette M. Tetrault, MD, FACP

Federico E. Vaca, MD, MPH

Professor and Vice Chair
Yale University, School of Medicine
Frank Vocci, PhD

President and Senior Research Scientist
Friends Research Institute, Inc.
Baltimore, Maryland
Nora D. Volkow, MD
Director
Bethesda, Maryland
Darren C. Volpe, MD
Assistant Professor of Neurology
Alexander Y. Walley, MD, MSc

Director, Addiction Medicine Fellowship
Clinical Addiction Research and Education Unit
Boston Medical Center/Boston University School of Medicine
Eric M. Wargo, PhD
Office of Science Policy and Communication, Science Policy Branch
Bethesda, Maryland
Elizabeth A. Warner, MD
Clinical Associate Professor
University of South Florida Morsani College of Medicine
Tampa, Florida
Alan A. Wartenberg, MD, FACP, DFASAM

Affiliated Faculty
Brown University Center for Alcohol and Addiction
Studies
Michael F. Weaver, MD, DFASAM

Professor of Psychiatry and Behavioral Science
McGovern Medical School
University of Texas Health Science Center at
Houston
Medical Director, Center for Neurobehavioral Research on Addiction
University of Texas Health Science Center at
Houston
Houston, Texas
Julia Megan Webb, MD

Pain Medicine Fellowship Graduate
Department of Anesthesiology and Pain Medicine
University of California Davis
Zoe M. Weinstein, MD, MS

Director, Addiction Consult Service
Roger D. Weiss, MD
Chief, Division of Alcohol and Drug Abuse
McLean Hospital
Arthur F. Weissman, MD
Clinical Assistant Professor
Addiction Medicine
University at Buffalo
Buffalo, New York
Sandra P. Welch, PhD

Professor, Department of Pharmacology and
Toxicology
Richmond, Virginia
Joseph Westermeyer, MD, MPH, PhD

Professor of Psychiatry, Adjunct Professor of Anthropology
Staff Psychiatrist
Addiction Recovery Service
Norman W. Wetterau, MD, FAAFP, DFASAM

Clinical Associate Professor of Family Medicine
University of Rochester School of Medicine
Rochester, New York
Physician
Tri-county Family Medicine
Nunda, New York
William L. White, MA
Emeritus Senior Research Consultant
Chestnut Health Systems
Punta Gorda, Florida
Ursula Whiteside, PhD

Clinical Faculty, Department of Psychiatry and Behavioral Sciences
University of Washington Medical Center
Seattle, Washington
Bonnie B. Wilford, MS
Coalition on Physician Education in Substance Use Disorders (COPE)
Easton, Maryland
Jeffery N. Wilkins, MD, DFAPA, DFASAM

Lincy/Heyward-Moynihan Endowed Chair in Addiction Medicine
Department of Psychiatry and Behavioral Neurosciences
Cedars-Sinai Medical Center
Mark Willenbring, MD
CEO and Founder
Alltyr Clinics
Saint Paul, Minnesota
Emily C. Williams, PhD, MPH

Investigator, Center of Innovation for Veteran-Centered and Value-Driven Care
Veterans Affairs, Health Services Research & Development
Associate Professor, Department of Health Services
Seattle, Washington
Ken C. Winters, PhD
Senior Scientist, Oregon Research Institute
Adjunct Faculty, Department of Psychology
Falcon Heights, Minnesota
John J. Woodward, BS, MS, PhD

Professor
Department of Neuroscience
Tara M. Wright, MD
Addiction Psychiatry Fellowship Director
Assistant Chief Mental Health Service Line
Martha J. Wunsch, MD
Chief of Addiction Medicine
Fellowship Director, Addiction Medicine
Kaiser Permanente, GSAA, Northern California
Union City, California
Stephen A. Wyatt, DO
Carolinas HealthCare System
Medical Director, Addiction Medicine
Atrium Health
Charlotte, North Carolina
Yvonne H.C. Yau, MSc

Montreal Neurological Institute
McGill University
Montreal, Quebec, Canada
Elmira Yessengaliyeva, MD
Kalamazoo, Michigan
Sarah W. Yip, MSc, PhD

Assistant Professor
Christine Yuodelis-Flores, MD, FAPA, FASAM

Associate Professor
Harborview Medical Center
Seattle, Washington
Anne Zajicek, MD, PharmD, FAAP

Deputy Director, Office of Clinical Research
Office of the Director
Bethesda, Maryland
Aleksandra E. Zgierska, MD, PhD

Assistant Professor
Department of Family Medicine and Community Health
University of Wisconsin-Madison, School of Medicine and Public Health
Madison, Wisconsin
Douglas Ziedonis, MD, MPH

Associate Vice Chancellor for Health Sciences
University of California San Diego
San Diego, California
Joan E. Zweben, PhD

Health Sciences Clinical Professor of Psychiatry
Staff Psychologist
VA Medical Center
† Deceased
Preface
Welcome to the sixth edition of Principles of Addiction Medicine. Our goal, as

with previous editions of Principles, is to provide a reference text that reflects
the state of the art in the science and practice of addiction medicine. This goal is
supported through the textbook’s link to the American Society of Addiction
Medicine (ASAM), the world’s largest addiction medicine professional
association, and through the involvement of the world’s leading researchers and
experts in our field. This edition of Principles is being released soon after the
American Board of Medical Specialties has formally recognized addiction
medicine as a medical specialty, more than half a century after the formation of
the American Society of Addiction Medicine.
The text is organized pyramidally under senior editor, coeditors, section
editors, and authors. As in previous editions, a new coeditor has joined the
editorial team. Richard Rosenthal provides his strengths in psychiatry and co-
occurring psychiatric disorders, behavioral and 12-step approaches, and
collaborative team-based care for addiction-related disorders. He returns to the
textbook after previous service as a section editor. Both Richard Saitz, MD, and
David Fiellin, MD, return as coeditors (having previously served as such in the
fourth and fifth editions) and provide cornerstones to our links to patient-
oriented research, screening and brief intervention, and the management of
opioid use disorders, while sharing their wide-ranging expertise in internal
medicine and primary care. Dr. Saitz also serves as senior editor of ASAM’s
peer-reviewed medical journal, Journal of Addiction Medicine (JAM). Shannon
Miller, MD, returns from the fourth and fifth editions where he served as
coeditor, and now serves as senior editor of this sixth edition of Principles. He
provides strengths in psychiatry and neuroscience, and his editorial link as a
founding coeditor of ASAM’s peer-reviewed medical journal, JAM.
The editors have updated, deleted, added, and moved chapters to provide
more coherence and completeness to the textbook experience, with updates to all
chapters and substantial revisions of most. Importantly, this edition has aimed to
incorporate DSM-5 language throughout its chapters, while attempting to
preserve linkages to previous DSM editions. To maintain Principles as a
reference textbook that remains current and relevant to readership as our field
rapidly expands in breadth and depth, a substantial number of new chapters have
been added with this sixth edition; several of which are first-time appearances
for these topics within any addiction-related textbook.
Kevin Kunz, MD, leads Section 1, “Basic Science and Core Concepts.” The
opening chapter, “Drug Addiction: The Neurobiology of Behavior Gone Awry,”
is written by Nora Volkow, MD, and George Koob, PhD, directors of the
National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol
Abuse and Alcoholism (NIAAA), respectively. In addition to orienting the
reader to basic principles in neurobiology and epidemiology of addiction,
important new chapters have been added on recommended use of terminology in
the field of addiction medicine (Chapter 2), understanding research in addiction-
related clinical trials (Chapter 6), and the addiction medicine physician as a
change agent toward public health (Chapter 7).
Thomas Kosten, MD, leads Section 2 on pharmacology along with David
Gorelick, MD, PhD, John Dani, PhD, and Daryl Shorter, MD. This team has
worked to better elucidate the clinical relevance of this section’s content to
readers. Expansion into increasingly important topics such as electronic
recreational drug delivery vehicles such as e-cigarettes (Chapter 20), synthetic
cannabis (Chapter 15), and dextromethorphan (Chapter 17) have been
incorporated; and the chapter on newly emerging recreational drugs has been
enriched (Chapter 21).
Section 3, Diagnosis, Assessment, and Early Intervention, is led by
Theodore Parran Jr, MD, and features expanded material on screening and brief
interventions in a variety of settings, laboratory testing, assessment, and
community-based prevention.
Wilson Compton, MD, MPE, from NIDA and Lori Ducharme, PhD, from
NIAAA lead Section 4 on Overview of Addiction Treatment. The section
includes chapters on historical and international perspectives on addiction
treatment with contributions from individuals affiliated with the United Nations
Office of Drug Control, the World Health Organization and the ASAM’s
international companion, the International Society of Addiction Medicine. Issues
such as treatment matching, integrated care, and quality improvement are
addressed. In addition, Chapter 33 on harm reduction includes pivotal content on
opioid overdose education and naloxone distribution—significantly expanded in
parallel with this national crisis.
In Section 5, “Special Issues in Addiction Medicine,” led by Joan Zweben,
PhD, Peter Banys, MD, MSc, and John Grant, MD, JD, MPH, places an
increased focus on nonsubstance addictions as a collective whole, while still
maintaining focus on special populations such as older adults, women, college
students, impaired providers, and cultural issues. Military-relevant new chapters
have been added on traumatic brain injury (Chapter 39) and military sexual
trauma (Chapter 40). Chapter 45 covering gambling disorder has been
significantly updated to reflect the acceptance of this disorder as an addiction
disorder in DSM-5. A new chapter on microprocessor-based disorders (Chapter
47) include the latest neuroimaging and neuropsychological findings supporting
the Internet gaming disorder diagnosis.
Adam Gordon, MD, and Andrew Saxon, MD, continue as the section editors
of Sections 6 and 7, respectively. The management and pharmacologic treatment
chapters in these sections have all been fully updated to include the most current
information. Section 6 includes discussion of not only FDA-approved
pharmacotherapies (such as buprenorphine and intramuscular naltrexone for
opioid use disorder) but also off-label uses of pharmacotherapies for addiction-
related disorders. Section 7 includes a novel chapter on neuromodulation as a
treatment approach to addiction disorders (Chapter 62), including transcranial
magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).
Richard Rosenthal, MD, leads Section 8 on psychologically based
interventions. The section incorporates the latest research in behavioral therapies
and adds a new chapter on digital health interventions for substance use
disorders (Chapter 74).
Richard Ries, MD, leads Section 9 on mutual help and 12-step recovery
programs with chapters on process and research evidence and contributes a
chapter on spirituality and recovery.
Section 10 is led by Jeanette Tetrault, MD, along with Patrick O’Connor,
MD, MPH, and includes fully updated content to include the latest research
about medical disorders and complications of addiction. This includes important
updates to the treatment of medical consequences of addiction, such as hepatitis
C and HIV; as well as approaches to the pregnant patient.
Section 11, led by R. Jeffrey Goldsmith, MD, and Christine Yuodelis-Flores,
MD, includes updated chapters on co-occurring addiction and mood, anxiety,
psychotic, personality, eating, and substance-induced disorders, respectively, as
well as ADHD and PTSD.
Section 12 maintains the support from Seddon Savage, MD, from past
editions but is now led by Rollin Gallagher, MD, along with William Becker,
MD, and Martin Cheatle, PhD, all of whom have also contributed chapters to the
section. The biopsychosocial intersections between pain and addiction are
explored in a comprehensive and cohesive manner. Legal and regulatory issues
in opioid prescribing are also addressed for the reader.
Deborah Simkin, MD, John Knight, MD, and Wes Boyd, MD, lead Section
13 on children and adolescents. This section has been interwoven with content in
other sections relating to subject matter on addiction-related issues in children
and adolescents. Relevant to today’s policy-making climate, the impact of
cannabis legalization and cannabis as medicine on youth are presented (Sidebar
to Chapter 107).
Bonnie Wilford, MS, Robert DuPont, MD, and Timothy Koehler Brennan,
MD, MPH, lead Section 14, “Ethical, Legal, and Liability Issues in Addiction
Practice,” which features an opening chapter by Timothy Brennan, MD, MPH,
and H. Westley Clark, MD, JD, former Director of the Center for Substance
Abuse Treatment under the Substance Abuse and Mental Health Services
Administration (Chapter 115), and a new chapter on cannabis use in medical
settings (Chapter 118).
A Note About Terminology
The editors of Principles of Addiction Medicine recognize that addiction is a
medical condition with its own terminology used by not only clinicians and
researchers but also patients, policy makers, the press, families, and other
stakeholders. There are certain key terms that can have several meanings and,
often unintended, effects. Most importantly, such terms can further the stigma
about people and patients with addiction disorders. The terms “alcoholic” and
“addict” are examples of such terms—they can be used by health care workers in
a pejorative manner to label a problem medical patient, by family to label a
member’s violent and irresponsible behavior, by persons with a substance use
disorder attending 12-step meetings as a positive label defining themselves as
actively participating in recovery, by the general public to define anybody “who
drinks too much” or “is a drug user,” and by addiction professionals to indicate a
patient’s substance use disorder. Pejorative terms can erode the motivation of
people affected by these disorders to come forward for help from family, friends,
or professionals. Inaccurate terms can cause confusion and lead to unclear
research results, difficulty translating such results into practice, and
inappropriate clinical care. Furthermore, inappropriate and imprecise terms can
dehumanize patients as well as undermine and erode efforts toward scientifically
informed and ethically appropriate public policy or legislation, including funding
for research, treatment, or graduate medical education.
However, we must confess that consensus definitions of the many terms in
addiction medicine have not yet been reached. As such, ASAM has
commissioned The Descriptive and Diagnostic Terminology Action Group to
continue to address these issues. This group has identified a number of terms that
have the potential to be inaccurate or even stigmatizing. In this sixth edition of
Principles, we are attempting to avoid such terms, in particular those that can be
stigmatizing, and instead use more medically appropriate and less stigmatizing
terms. This is among the first textbooks in the field to embark more formally
upon this aim, including dedicating a chapter to introduce this issue (Chapter 2).
Addiction medicine is shaped by constantly evolving science and practical
clinical experience. It is our sincere hope that this book will embody the best of
what both of these can offer to clinicians as we work to serve our patients and
society.
Acknowledgments
The editors wish to thank the American Society of Addiction Medicine (ASAM)
for the opportunity to work on this textbook. Our section editors and authors
generously lent their time and expertise. Chris Teja and Rebecca Gaertner at
Lippincott Williams & Wilkins helped bring the project to fruition. Yemsrach
Kidane, MA, Manager of Quality and Science at ASAM skillfully nurtured most
every aspect of this textbook from beginning to end; and under the sage
stewardship and tireless advocacy of Brendan McEntee, Director of Quality and
Science at ASAM. Finally, we wish to acknowledge the contributions of the
editors of previous editions of Principles of Addiction Medicine; with enduring
respect and recognition Norman S. Miller, MD; Martin C. Doot, MD; Bonnie B.
Wilford, MS; Allan W. Graham, MD, FACP; Terry K. Schultz, MD; Michael F.
Mayo-Smith, MD, MPH; and Richard K. Ries, MD.
Contents
Section Editors
Contributors
Preface
A Note About Terminology
Acknowledgments
SECTION 1
Basic Science and Core Concepts
1 Drug Addiction: The Neurobiology of Motivation Gone

Awry
Nora D. Volkow and George F. Koob
2 Recommended Use of Terminology in Addiction Medicine

Richard Saitz, Shannon C. Miller, David A. Fiellin, and Richard N. Rosenthal
3 The Epidemiology of Substance Use Disorders

Rosa M. Crum
4 The Anatomy of Addiction

Thomas J.R. Beveridge, Colleen A. Hanlon, and David C.S. Roberts
5 From Neurobiology to Treatment: Progress against

Addiction
Drew D. Kiraly and Eric J. Nestler
6 Clinical Trials in Substance-Using Populations

Frank Vocci
7 The Addiction Medicine Physician as a Change Agent for

Prevention and Public Health
Kevin Kunz
SECTION 2
Pharmacology
8 Pharmacokinetic, Pharmacodynamic, and

Pharmacogenomic Principles
Anne Zajicek and Lori D. Karan
9 The Pharmacology of Alcohol

John J. Woodward
10 The Pharmacology of Nonalcohol Sedative Hypnotics

Carolina L. Haass-Koffler and Elinore F. McCance-Katz
11 The Pharmacology of Opioids

Daryl Shorter and Thomas R. Kosten
12 The Pharmacology of Stimulants

David A. Gorelick and Michael H. Baumann
13 The Pharmacology of Caffeine

Mary M. Sweeney, Laura M. Juliano, Sergi Ferré, and Roland R. Griffiths
14 The Pharmacology of Nicotine and Tobacco

John A. Dani, Thomas R. Kosten, and Neal L. Benowitz
15 The Pharmacology of Cannabinoids

Sandra P. Welch, Tricia H. Smith, Robert Malcolm, and Aron H. Lichtman
16 The Pharmacology of Hallucinogens

Michael P. Bogenschutz and David E. Nichols
17 The Pharmacology of Dissociatives

Edward F. Domino and Shannon C. Miller
18 The Pharmacology of Inhalants

Robert L. Balster
19 The Pharmacology of Anabolic–Androgenic Steroids

Scott E. Lukas
20 Electronic Cigarettes
Gideon St.Helen and Neal L. Benowitz
21 Novel Psychoactive Substances: Their Recognition,

Pharmacology, and Treatment
Kathryn Hawk, Barbara M. Kirrane, and Gail D’Onofrio
SECTION 3
Diagnosis, Assessment, and Early Intervention
22 Screening and Brief Intervention

Suena H. Massey, Nicole A. Hayes, Michael F. Fleming, and Aleksandra E. Zgierska
SIDEBAR: Screening and Brief Intervention for Pregnant Women

Nicolas Bertholet and Richard Saitz
SIDEBAR: Trauma Centers, Hospitals, and Emergency Departments

Arthur F. Weissman and Richard D. Blondell
SIDEBAR: Implementation of Screening and Brief Intervention (SBI) in Clinical Settings Using
Quality Improvement Principles
Emily C. Williams and Katharine A. Bradley
SIDEBAR: Screening for Unhealthy Alcohol Use in the Elderly

James W. Campbell
23 Laboratory Assessment
Jessica S. Merlin, Elizabeth A. Warner, and Joanna L. Starrels
24 Assessment
Theodore V. Parran Jr, Mark Bondeson, Richard A. McCormick, and Christina M. Delos Reyes
25 Environmental Approaches to Prevention: Communities

and Contexts
Paul J. Gruenewald, Joel W. Grube, Robert F. Saltz, and Mallie J. Paschall
SECTION 4
Overview of Addiction Treatment
26 Addiction Medicine in America: Its Birth, Early History,

and Current Status (1750-2018)
Kevin Kunz and William L. White
27 Treatment of Unhealthy Alcohol Use: An Overview

Mark Willenbring and Brian Grahan
28 The Treatment of Addiction: An Overview

Andrea G. Barthwell, Lawrence S. Brown Jr and Megan E. Crants
29 Integrated Care for Substance Use Disorder

Keith Humphreys, Mark McGovern and A. Thomas McLellan
30 The ASAM Criteria and Matching Patients to Treatment

David Mee-Lee and Gerald D. Shulman
31 Linking Addiction Treatment With Other Medical and

Psychiatric Treatment Systems
Karran A.Phillips, Peter D. Friedmann, Richard Saitz, and Jeffrey H. Samet
32 Alternative Therapies for Substance Use Disorders

David Y.W. Lee
33 Harm Reduction, Overdose Prevention, and Addiction

Medicine
Alexander Y. Walley, Sharon Stancliff, and India Perez-Urbano
34 Quality Improvement for Addiction Treatment

James H. Ford II, Kim A. Hoffman, Kimberly Johnson, and Javier Ponce Terashima
35 Nursing Roles in Addressing Addiction

Deborah S. Finnell, Marianne T. Marcus, and Christine L. Savage
36 International Perspectives on Addiction Management

Nady el-Guebaly, Vladimir Poznyak, and Gilberto Gerra
SECTION 5
Special Issues in Addiction
37 Prescription Medications: Nonmedical Use, Use Disorders,

and Public Health Consequences
Wilson M. Compton, Christopher M. Jones, Maureen P. Boyle, and Eric M. Wargo
38 Special Issues in Treatment: Women

Joan E. Zweben
39 Traumatic Brain Injury and Substance Use Disorders

David L. Pennington, Tatjana Novakovic-Agopian, and Steven L. Batki
40 Military Sexual Trauma
Joan E. Zweben
41 Alcohol, Prescription, and Other Drug Problems in Older

Adults
Frederic C. Blow and Kristen L. Barry
42 Cultural Issues in Addiction Medicine

Joseph Westermeyer and Patricia Jean Dickmann
43 College Student Drinking

Frank J. Schwebel, Ursula Whiteside, Joyce N. Bittinger, Jason R. Kilmer, Ty W. Lostutter, and Mary
E. Larimer
44 Understanding “Behavioral Addiction”

Yvonne H.C. Yau, Sarah W. Yip, and Marc N. Potenza
45 Gambling Disorder: Clinical Characteristics and Treatment

Jon E. Grant and Brian L. Odlaug
46 Problematic Sexual Behaviors and “Sexual Addiction”

Timothy M. Hall, Simone H. Schriger, and Steven Shoptaw
47 Microprocessor-Based Disorders
Richard N. Rosenthal, Zebulon Charles Taintor, and Jon E. Grant
48 Behavioral Syndromes to Consider as Forms of “Addiction”

Abigail J. Herron, Paul J. Rinaldi, and Petros Levounis
49 Physician Health Programs and Addiction Among

Physicians
Paul H. Earley
SECTION 6
Management of Intoxication and Withdrawal
50 Management of Intoxication and Withdrawal: General

Principles
Tara M. Wright, Jeffrey S. Cluver, and Hugh Myrick
51 Management of Alcohol Intoxication and Withdrawal

Alan A. Wartenberg
52 Management of Sedative–Hypnotic Intoxication and
Withdrawal
Steven J. Eickelberg, William E. Dickinson, and Reham A. Attia
53 Management of Opioid Intoxication and Withdrawal

Jeanette M. Tetrault and Patrick G. O’Connor
54 Management of Stimulant, Hallucinogen, Marijuana,

Phencyclidine, and Club Drug Intoxication and Withdrawal
Jeffery N. Wilkins, Itai Danovitch, and David A. Gorelick
SECTION 7
Pharmacological Interventions and Other Somatic Therapies
55 Pharmacological Interventions for Alcohol Use Disorder

Hugh Myrick, Andrew J. Saxon, and Jerome H. Jaffe
56 Pharmacological Interventions for Sedative–Hypnotic Use

Disorder
Jeffrey S. Cluver, Tara M. Wright, and Hugh Myrick
57 Pharmacological and Psychosocial Treatment for Opioid

Use Disorder
David Kan, Joan E. Zweben, Susan M. Stine, Thomas R. Kosten, Elinore F. McCance-Katz, and
John J. McCarthy
58 Special Issues in Office-Based Opioid Treatment

Andrew J. Saxon
59 Pharmacological Treatment of Stimulant Use Disorders

David A. Gorelick
60 Pharmacological Interventions for Tobacco Use Disorder

Jon O. Ebbert, J. Taylor Hays, David D. McFadden, Ryan T. Hurt, and Richard D. Hurt
61 Pharmacological Interventions for Other Drugs and

Multiple Drug Use Disorders
Jeffery N. Wilkins, Mark Hrymoc, and David A. Gorelick
62 Neuromodulation for Addiction-Related Disorders

David A. Gorelick
SECTION 8
Psychologically Based Interventions
63 Enhancing Motivation to Change

James O. Prochaska
64 Group Therapies
Dennis C. Daley, Antoine Douaihy, Roger D. Weiss, and Delinda E. Mercer
65 Individual Treatment
Deborah L. Haller and Edward V. Nunes
66 Contingency Management and the Community

Reinforcement Approach
Sarah H. Heil, Danielle R. Davis, Christopher A. Arger, and Stephen T. Higgins
67 Behavioral Interventions for Nicotine/Tobacco Use Disorder

Erika Litvin Bloom, Christopher W. Kahler, Adam M. Leventhal, and Richard A. Brown
68 Network Therapy
Marc Galanter and Helen Dermatis
69 Therapeutic Communities and Modified Therapeutic

Communities for Co-Occurring Mental and Substance Use
Disorders
George De Leon and Stanley Sacks
70 Aversion Therapies
P. Joseph Frawley, Matthew Owen Howard, Ralph L. Elkins, and Kalyan Dandala
71 Family Involvement in Addiction, Treatment, and Recovery

Kathleen A. Gross, Maritza E. Lagos, Elmira Yessengaliyeva, Matthew M. LaCasse, and Michael R.
Liepman (deceased)
72 Twelve-Step Facilitation Approaches

Kathleen M. Carroll
73 Relapse Prevention: Clinical Models and Intervention

Strategies
Antoine Douaihy, Dennis C. Daley, G. Alan Marlatt, and Dennis M. Donovan
74 Digital Health Interventions for Substance Use Disorders:

The State of the Science
Lisa A. Marsch and Jacob T. Borodovsky
75 Medical Management Techniques and Collaborative Care:

Integrating Behavioral with Pharmacological Interventions
in Addiction Treatment
Richard N. Rosenthal, Richard K. Ries, and Joan E. Zweben
SECTION 9
Mutual Help, Twelve-Step, and Other Recovery Programs
76 Twelve-Step Programs in Addiction Recovery

Edgar P. Nace
77 Recent Research into Twelve-Step Programs

Barbara S. McCrady
78 Spirituality in the Recovery Process

Marc Galanter
SECTION 10
Medical Disorders and Complications of Addiction
79 Medical and Surgical Complications of Addiction

Richard Saitz
80 Cardiovascular Consequences of Alcohol and Other Drug

Use
Steven Pfau and Samit Shah
81 Liver Disorders Related to Alcohol and Other Drug Use

Paul S. Haber and Carl H. Freyer
82 Renal and Metabolic Disorders Related to Alcohol and

Other Drug Use
Laith Al-Rabadi, Catreena Al Marj, Girish Singhania, A. Ahsan Ejaz, and Stanley D. Crittenden
83 Gastrointestinal Disorders Related to Alcohol and Other

Drug Use
Paul S. Haber and Praveen Gounder
84 Respiratory Tract Disorders and Selected Critical Care
Considerations Related to Alcohol and Other Drug Use
Drew A. Harris, Jason J. Heavner, and Kathleen M. Akgün
85 Neurological Disorders Related to Alcohol and Other Drug

Use
Emmanuelle A.D. Schindler, Monica M. Diaz, Brian C. Mac Grory, Brian B. Koo, Darren C. Volpe,
Hamada Hamid Altalib, Huned S. Patwa, and Jason J. Sico
86 Human Immunodeficiency Virus, Tuberculosis, and Other

Infectious Diseases Related to Alcohol and Other Drug Use
Carol A. Sulis and Simeon D. Kimmel
87 Sleep Disorders Related to Alcohol and Other Drug Use

Sanford Auerbach and Yelena Gorfinkel Pyatkevich
88 Traumatic Injuries Related to Alcohol and Other Drug Use:

Epidemiology, Screening, and Prevention
Federico E. Vaca, Deepa Camenga, and Gail D’Onofrio
89 Endocrine and Reproductive Disorders Related to Alcohol

and Other Drug Use
Alan Ona Malabanan and Gwendolyne Anyanate Jack
90 Alcohol and Other Drug Use during Pregnancy:

Management of the Mother and Child
Michael F. Weaver, Hendrée E. Jones, and Martha J. Wunsch
91 Perioperative Management of Patients with Alcohol- or

Other Drug Use
Daniel P. Alford and Zoe M. Weinstein
SECTION 11
Co-Occurring Addiction and Psychiatric Disorders
92 Substance-Induced Mental Disorders

Christine Yuodelis-Flores, R. Jeffrey Goldsmith, and Richard K. Ries
93 Co-occurring Mood and Substance Use Disorders

Edward V. Nunes and Roger D. Weiss
94 Co-Occurring Substance Use and Anxiety Disorders
Karen J. Hartwell, Dennis E. Orwat, and Kathleen T. Brady
95 Co-Occurring Addiction and Psychotic Disorders

Douglas Ziedonis, Xiaoduo Fan, Celine Larkin, Stephen A. Wyatt, and David Smelson
96 Co-occurring Substance Use Disorder and Attention Deficit

Hyperactivity Disorder
Frances R. Levin and John J. Mariani
97 Co-occurring Personality Disorders and Addiction

Stephen Ross and Adam R. Demner
98 Posttraumatic Stress Disorder and Substance Use Disorder

Comorbidity
Michael Saladin, Jenni Teeters, Daniel F. Gros, Amanda K. Gilmore, Kevin M. Gray, Emma Louise
Barrett, Cynthia L. Lancaster, Therese Killeen, and Sudie Back
99 Co-occurring Substance Use Disorders and Eating

Disorders
Lisa J. Merlo and Mark S. Gold
SECTION 12
Pain and Addiction
100 The Pathophysiology of Chronic Pain and Clinical

Interfaces With Substance Use Disorder
Rollin M. Gallagher, Peggy Compton, and Adrian Popescu
101 Psychological Issues in the Management of Pain

Martin D. Cheatle
102 Rehabilitation Approaches to Pain Management

Steven P. Stanos and Randy L. Calisoff
103 Nonopioid Pharmacotherapy of Pain

Simy K. Parikh, Michael Perloff, and James A.D. Otis
104 Opioid Therapy of Pain

Peggy Compton and Friedhelm Sandbrink
105 Co-Occurring Pain and Addiction

William C. Becker and Declan T. Barry
106 Legal and Regulatory Considerations in Opioid Prescribing

Julia Megan Webb, David J. Copenhaver, Wesley Prickett, and Scott M. Fishman
SECTION 13
Children and Adolescents
107 Preventing Substance Use Among Children and Adolescents

Kenneth W. Griffin and Gilbert J. Botvin
SIDEBAR: Governmental Policy on Cannabis Legalization and Cannabis as Medicine: Impact on

Youth
Sion Kim Harris, Julie K. Johnson, and John R. Knight Jr
108 Translational Neurobiology of Addiction from a

Developmental Perspective
Deborah R. Simkin
109 Screening and Brief Intervention for Adolescents

Traci L. Brooks, John R. Knight Jr, and Sion Kim Harris
110 Assessing Adolescent Substance Use

Ken C. Winters, Andria M. Botzet, Randy Stinchfield, and Walker H. Krepps
111 Placement Criteria and Strategies for Adolescent Treatment

Matching
Marc Fishman
SIDEBAR: Confidentiality in Dealing with Adolescents

Margaret R. Moon
SIDEBAR: Drug Testing Adolescents in School

J. Wesley Boyd and John R. Knight Jr
112 Adolescent Treatment and Relapse Prevention

Steven L. Jaffe and Ashraf Attalla
113 Pharmacotherapies for Adolescents with Substance Use

Disorders
Geetha A. Subramaniam and Kevin M. Gray
114 Co-occurring Psychiatric Disorders in Adolescents

Ramon Solhkhah and Muhammad A. Abbas
SECTION 14
Ethical, Legal, and Liability Issues in Addiction Practice
115 Ethical Issues in Addiction Practice

Timothy K. Brennan and H. Westley Clark
116 Consent and Confidentiality Issues in Addiction Practice

Louis E. Baxter Sr, Mark F. Seltzer Esq, and Bonnie B. Wilford
117 Clinical, Ethical, and Legal Considerations in Prescribing

Drugs With Potential for Nonmedical Use and Addiction
Theodore V. Parran Jr, James W. Finch, and Bonnie B. Wilford
SIDEBAR: Drug Control Policy: History and Future Directions

John J. Coleman and Robert L. DuPont
SIDEBAR: Guidance on the Use of Opioids to Treat Chronic Pain

James W. Finch and Bonnie B. Wilford
118 Medicinal Uses of Cannabis and Cannabinoids

Jag H. Khalsa, Gregory C. Bunt, Marc Galanter, and Norman W. Wetterau
119 Practical Considerations in Drug Testing

Gary M. Reisfield, Roger L. Bertholf, Bruce A. Goldberger, and Robert L. DuPont
SIDEBAR: Workplace Drug Testing and the Role of the Medical Review Officer
James L. Ferguson and Robert L. DuPont
120 Reducing Substance Use in Criminal Justice Populations

Beau Kilmer, Jonathan P. Caulkins, Robert L. DuPont, and Keith Humphreys
SIDEBAR: Treatment of Substance Use Disorders During Incarceration

Lori D. Karan
121 Preventing and Treating Substance Use Disorders in

Military Personnel
Kenneth Hoffman, Robert M. Bray, and Janet H. Lenard
SIDEBAR: Risk Factors for Military Families

Joan E. Zweben and Susan A. Storti
Index
SECTION 1
Basic Science and Core Concepts

CHAPTER 1
Drug Addiction: The Neurobiology of
Motivation Gone Awry
Nora D. Volkow and George F. Koob
CHAPTER OUTLINE
Introduction
Addiction: A Developmental Disorder
Neurobiology of Addictive Drugs: Binge–Intoxication Stage
Neurobiology of Drug Addiction: Withdrawal–Negative Affect Stage
Neurobiology of Drug Addiction: Preoccupation–Anticipation (“Craving”)
Stage
Vulnerability to Addiction
Strategies to Combat Addiction
Challenges for Society
Summary
INTRODUCTION
Drug addiction manifests as a chronic relapsing disorder, characterized by a
compulsive drive to take a drug despite serious adverse consequences, the loss of
control over intake, and the emergence of a negative emotional state during
abstinence. This aberrant behavior has traditionally been viewed as a bad
“choice” that is made voluntarily by the addicted person, a view that engendered
the lingering stigma of addiction as a moral failure. However, addiction
researchers have collected converging evidence that shows that frequent drug
misuse changes the brain in ways that can lead to the profound behavioral
disruptions that are seen in addicted individuals. This is because addictive drugs
impact many neuronal circuits, including those that are involved in processing
responses to rewarding stimuli and motivating behavioral actions, negative
emotions, interoception, decision-making, and cognitive control, turning drug
use into compulsive behavior. The fact that these changes are progressive but
that, once developed, are long lasting, persisting even after years of drug use
discontinuation, is what makes addiction a chronic and relapsing disease but also
one that offers unique opportunities for prevention. New knowledge about
vulnerability factors that increase the risk for drug use and addiction, including
genetic, developmental, and environmental factors, and our much better
understanding of the effects of drugs in the brain has started to bring about
changes in our approaches to the prevention, diagnosis, and treatment of
substance use disorders (SUDs; new terminology used by the Diagnostic and
Statistical Manual of Mental Disorders, 5th edition [DSM-5]), including
addiction (corresponding roughly to moderate to severe SUD).
Drugs, both legal (eg, alcohol, nicotine) and illegal (eg, cocaine,
methamphetamine, heroin, marijuana), and psychotherapeutics (opioid
analgesics, stimulant medications, benzodiazepines, and barbiturates) can be
used for various reasons, including to experience pleasure, alter mental states,
improve performance, and self-medicate negative emotional states or a mental
disorder. The repeated use of a psychoactive drug in vulnerable individuals can
result in addiction, which is characterized by an intense desire for the drug,
combined with an impaired ability to control that urge, even in the face of well-
known adverse, even catastrophic consequences (eg, incarceration, loss of child
custody, loss of medical license, adverse health effects).
It is important to emphasize the distinct difference between a state of
addiction and a state of physical dependence. Physical dependence results in
strong withdrawal symptoms when drugs, such as alcohol and heroin, are
discontinued, but the adaptations that are responsible for these effects are
relatively short lasting and distinct from those that underlie addiction, which are
much longer lasting and are described in detail in this chapter. Partly because
this distinction has often led to confusion, the DSM-5 eliminated the categories
of substance abuse and dependence and uses instead the category of “addiction
and related disorders.” This nomenclature strategy, which includes SUD (with
each drug identified in its own category along with its severity), may better
capture the dimensionality of the disease, variations in disease severity, and the
complex progression of neural and behavioral impairments that afflict addicted
individuals.
A growing body of basic research in animal models and imaging evidence in
humans provides critical insights that help explain the aberrant behavioral
manifestations that characterize addiction. The convergent results suggest that
individuals with addiction undergo progressive structural and functional
disruption in brain regions that underlie normal processes of reward and
motivation, emotional regulation, inhibitory control, and self-awareness (1,2).
Drug addiction has been conceptualized as a cycle of three stages, each
representing basic neurocircuitry linked to a functional domain and associated
brain functional networks, but with the recognition that brain networks interact
with one another (Fig. 1-1). The binge–intoxication stage via the neurocircuitry
of the basal ganglia reflects the rewarding effects of drugs and the ways in which
drugs impart motivational significance to cues and contexts in the environment,
termed incentive salience, which is experienced as “well-being,” “high,”
“euphoria,” or “relief,” depending on the degree of tolerance to the rewarding
effects of the drug (see Fig. 1-1). The withdrawal–negative affect stage via the
extended amygdala and habenula reflects the loss of reward and motivation and
the enhanced sensitivity and recruitment of the brain stress systems, termed a
negative emotional state, which is experienced as dysphoria, anhedonia, and
irritability (see Fig. 1-1). The preoccupation–anticipation (“craving”) stage via
the neurocircuitry of the prefrontal cortex (PFC) reflects the impulsivity and loss
of control over drug taking, termed loss of executive control, and the input from
the default mode network (DMN) that reflects the enhanced interoceptive
awareness of the desire for the drug, which is experienced as drug craving (see
Fig. 1-1) (3).
Figure 1-1. Conceptual framework for Neurobiology of

Addiction. The three stages of the addiction cycle (see text)
are linked to three domains of neurocircuity, which mediate
three domains of dysfunction: binge–intoxication (basal
ganglia–incentive salience), withdrawal–negative affect
(extended amygdala–negative emotional states),
preoccupation–anticipation (“craving”) (prefrontal cortex–
executive dysfunction). In parallel, the disruption of the
default mode network (DMN) necessary for interoceptive
awareness makes it harder to ignore drug craving as well as
the negative emotional states during the withdrawal-negative
affect stage. See eBook for color images.
This provides a compelling rationale for the argument that drug addiction is a
chronic disease of the brain (because the changes are long-lasting, persisting
months or years after drug discontinuation) and that the associated abnormal
behaviors (such as those that are associated with opioid, cocaine or alcohol use
disorders) are the result of dysfunctions in brain functional networks that are
necessary for everyday activities and in that way not different from cardiac
insufficiency, which is the result of impaired myocardial function that is
necessary for the heart to provide proper circulation to the rest of the body (4)
(Fig. 1-2). Therefore, although initial drug experimentation and recreational use
may be controllable in most cases, once addiction develops, behavioral control
becomes markedly disrupted. Importantly, although imaging studies consistently
show specific abnormalities in the brain in individuals with addiction, not all
people with addiction present these abnormalities, and the severity is not the
same across all addicted subjects. The dimensional and heterogeneous nature of
this disease has implications for its prevention and treatment and for public
health policy, highlighting the need for further research to delineate the nature
and diversity of genetic, neurobiological, and social factors that are involved in
addiction.
Figure 1-2. Drug addiction as a disease of the brain. Images
of the brain in a healthy control and in an individual addicted
to cocaine (top panel) and in an individual acutely exposed
to placebo or alcohol (middle panel) and parallel images of
the heart in a healthy control and in an individual with a
myocardial infarction (bottom panel). The images were
obtained with positron emission tomography (PET) and
[18F]fluoro-2-deoxyglucose (FDG-PET) to measure glucose
metabolism, which is a sensitive indicator of damage to the
tissue in the brain and the heart. Note the decreased glucose
metabolism in the orbitofrontal cortex (OFC) of the addicted
person and the decreased metabolism in the myocardial tissue
in the person with a myocardial infarct. Damage to the OFC
will result in improper inhibitory control and compulsive
behavior, and damage to the myocardium will result in
improper blood circulation. Although abnormalities in the
OFC are some of the most consistent findings in imaging
studies of addicted individuals (including alcohol addiction),
they are not detected in all addicted individuals. This implies
that disruption of this frontal region is not the only
mechanism that underlies the addictive process. See eBook
for color images. (Heart images courtesy of H. Schelbert,
University of California at Los Angeles. Images of glucose
metabolism during alcohol intoxication reprinted from
Volkow ND, et al. Acute alcohol intoxication decreases
glucose metabolism but increases acetate uptake in the
human brain. Neuroimage. 2013;64:277-283. Ref. (5).)
Drug addiction develops as a progressive process that involves complex

interactions between biological and environmental factors (6). This can help
explain why some individuals become addicted and why others do not and why
attempts to understand addiction as a purely biological or environmental disease
have been largely unsuccessful. Recently, important discoveries have provided a
means of explaining this environmental/biological interaction via our better
knowledge of the ways in which drugs affect the epigenome, the expression
patterns of specific genes, their protein products, neuronal communication and
plasticity, and neural circuitry (7) and the ways in which these biological factors
might conflate to affect human behavior. This also sets the stage for a better
understanding of the ways in which different environmental factors influence
molecular traits (eg, through epigenetic modifications (8)) and contribute to
patterns of behavior that facilitate the establishment of addiction.
Here, we summarize new methodologies that allow us to study how drugs
affect genes, their products, and the function of the human brain and how they
have provided us with a better understanding of drug addiction along with their
implications for the prevention and treatment of SUD.
ADDICTION: A DEVELOPMENTAL
DISORDER
Normal developmental processes might result in a higher risk of drug use at
certain times in life than others. Experimentation often starts in adolescence, as
does the process of addiction (9,10) (Fig. 1-3). Normal adolescent-specific
behaviors (such as risk taking, novelty seeking, and heightened sensitivity to
peer pressure) increase the likelihood of experimenting with legal and illegal
drugs (11,12), which likely reflects the incomplete development and connections
between brain regions (eg, pruning of frontal cortical regions and myelination of
projections that connect cortical and limbic brain regions) (13,14) that are
involved in the processes of executive control and necessary for regulating
emotions and desires. The frontal lobes and connections between the frontal
lobes do not fully develop until the age of 25 (13). This is relevant because drug
experimentation emerges in adolescence, and the highest rates of drug use for
most substances occur between 18 and 24 years of age, when the connectivity
between functional networks is still developing. Preclinical studies with animal
models and human imaging studies indicate that drug exposure during
adolescence might result in different neuroadaptations from those that occur
during adulthood. For example, adolescent rats that are exposed to nicotine
exhibit significant changes in nicotinic receptors, with greater reinforcement
value for nicotine later in life (15). Lasting reductions of synaptic metabotropic
glutamate receptor type 2 are also observed in the medial PFC, leading to
attention deficits later in adulthood (16). Similarly, recent studies in both humans
and animals have demonstrated that the adolescent period is distinctly sensitive
to long-term alterations by chronic alcohol and drug exposure (17–20) and may
explain the greater vulnerability to alcohol use disorder among individuals who
start using alcohol and drugs, including marijuana, early in life (19,21). For
example, adolescents who had engaged in episodes of heavy drinking presented
faster declining volumes in lateral frontal and temporal cortex gray matter
regions and smaller increases in regional white matter volumes relative to
nondrinking adolescents (22).
Figure 1-3. Mean age at first use for specific illicit drugs
among past year initiates aged 12-49, in 2011. (Data from
SAMHSA. Results from the 2011 National Survey on Drug
Use and Health: Summary of National Findings and Detailed
Tables. Rockville, MD: Substance Abuse and Mental Health
Services Administration, Office of Applied Studies, 2012.)
NEUROBIOLOGY OF ADDICTIVE
DRUGS: BINGE–INTOXICATION STAGE
During the binge–intoxication stage, large surges of dopamine (DA) and the
release of opioid peptides have been consistently associated with the reinforcing
effects of most addictive drugs. Addictive drugs induce large increases in
extracellular DA concentrations in the basal ganglia, including the nucleus
accumbens (NAc) (23,24). Specifically, the reinforcing effects of these drugs are
seemingly attributable to their ability to surpass the magnitude and duration of
the fast DA increases that occur in the NAc when triggered by natural
reinforcers, such as food and sex, that are necessary to stimulate DA D1
receptors that are needed for reward (25). Such drugs as cocaine, amphetamine,
methamphetamine, and ecstasy increase DA in the synaptic space by inhibiting
DA reuptake or by promoting the release of intravesicular DA into the cytoplasm
(26–28). Other drugs, such as nicotine, alcohol, opioids, and marijuana, work
directly or indirectly to modulate DA cell firing through their effects on
nicotinic, γ-aminobutyric acid (GABA), opioid, and cannabinoid receptors
(predominantly CB1), respectively (29,30). For example, alcohol has prominent
effects on DA and opioid peptide release in the basal ganglia (Fig 1-4 (31) and
Fig. 1-5 (32)), whereas heroin directly stimulates μ opioid receptors (MORs),
resulting in increases in DA in brain reward regions.
Figure 1-4. Neuroimaging of reward activation (binge–

intoxication stage). Alcohol releases DA in the striatum in
humans. Left, striatal change in [11C]raclopride
nondisplaceable binding potential (BPND) maps and
subjective activation in response to alcohol. The placebo
consisted of cranberry juice and soda alone, while the alcohol
drink in addition contained the equivalent of three standard
drinks of 100 proof vodka designed to deliver an average of
0.75 g alcohol per kg body water. BAL peaked at 55 minutes
after drink (1.15 ± 0.3 mg/mL in men and 1.02 ± 0.4 mg/mL
in women). BPND maps averaged across men (n = 11, top)
and women (n = 10, bottom) following placebo drink (left)
and alcohol drink (right). The MRI images (center) are
averaged across all 21 subjects. Images were all nonlinearly
warped into MNI space in the SPM2 software environment
(31). The ROIs on the coronal MRI image (left) are the
preDCA, preDPU, and VST. The line through the sagittal
MRI slice (right) shows the coronal slice level of the other
images. The graphs on the right show the correlation between
subjective activation at 30 minutes after drink (total score
post alcohol minus total score post placebo, not adjusted for
baseline) and absolute Δ BPND (reflecting changes in DA).
The relationship is stronger for men (top). Note that the
absolute value of Δ BPND is presented here. See eBook for
color images. (Taken from Urban NB, et al. Sex differences
in striatal dopamine release in young adults after oral alcohol
challenge: a positron emission tomography imaging study
with [11C]raclopride. Biol Psychiatry. 2010;68:689-696, with
permission.)
Figure 1-5. Neuroimaging of reward activation (binge–
intoxication stage). Alcohol consumption induces opioids in
the NAc in humans. Changes in MOR binding in ROIs
following alcohol consumption A. (Top). Spatially
coregistered coronal MRI (left) and PET (right) images from
a single representative control subject indicating designation
of individually drawn NAc ROIs. Left: Coronal section MRI
with the NAc ROI in orange. Right: [11C]carfentanil binding
potential, with highest binding potential in hot colors (see
color scale). (B) Binding potential (BP = Bmax/Kd − 1) for
the NAc region *p < 0.05; **p < 0.01, paired t tests for heavy
drinking (n = 12) and control subjects (n = 13) before and
after alcohol consumption. Alcohol consumption of one
standard drink in fruit juice resulted in blood alcohol levels of
0.04-0.05 gm%.
It is common to describe the effects of DA in the NAc as one that signals

“reward,” but this traditional concept is an oversimplification (33). Rather, DA is
a versatile modifier of motivation and a predictor of reward, and its effects
depend on the receptor through which it signals (there are five different DA
receptors). Psychopharmacological studies show that, depending on the
magnitude and time course of DA-mediated neuronal activity, the system can
encode different kinds of information to subcortical and cortical brain structures
that convey different messages about stimulus–response, approach behavior,
learning, and decision-making (34–36). For example, abrupt and large increases
in DA stimulate D1 receptors and are related to reward-predictive stimuli,
whereas slower and lower increases in DA stimulate D2 receptors and are related
to preparedness of the neuronal system to stimulation and are necessary for
sustaining effort and attention. Dopaminergic neurons also respond to aversive
stimuli or the absence of an expected reward by decreasing DA release, thus
influencing subsequent behaviors to avoid aversive stimuli or to avoid placing
effort on nonrewarding stimuli. Interestingly, imaging studies with individuals
who are diagnosed with cocaine addiction have shown the expected, drug-
induced fast increases in DA in the striatum (including the NAc) associated with
the drug’s rewarding effect, and such increases are markedly blunted compared
with controls (37) (see below). These same subjects with drug addiction,
however, present significant increases in DA in the striatum in response to drug-
conditioned cues that are associated with self-reports of drug craving and appear
to have a greater magnitude than DA responses to consumption of the drug itself.
We postulate that the discrepancy between the expectation for the drug’s effects
(ie, conditioned responses) and the blunted pharmacological effects of the drug’s
consumption maintain drug taking in an attempt to obtain the expected reward
(see Preoccupation-Anticipation Stage section).
Another important question can be posed: If natural reinforcers increase DA,
then why would they not lead to addiction? The difference might be attributable
to qualitative and quantitative differences in the increases in DA that are induced
by drugs, which are greater in magnitude (by at least 5- to 10-fold as measured
by microdialysis) and duration than are those that are induced by natural
reinforcers (25). Additionally, increases in DA that are produced by natural
reinforcers in the NAc undergo satiation, whereas those that are induced by
drugs of abuse do not (23). For natural reinforcers (but not for drugs) lower DA
release in NAc is associated with satiety (highly rewarding food that is rich in fat
and sugar is a special case that is discussed elsewhere in more detail) (38).
Finally, engagement of the dorsal striatum during addiction is thought to
help solidify habitual behaviors that are associated with drug seeking and taking.
Neuroadaptations in the dorsal striatum and NAc involve changes in glutamate,
GABA, and the endocannabinoid system (39,40).
NEUROBIOLOGY OF DRUG
ADDICTION: WITHDRAWAL–
NEGATIVE AFFECT STAGE
Addiction to drugs has been conceptualized as a reward deficit disorder (41).
More specifically, a defining characteristic of drug addiction is the transition
from impulsive drug intake to compulsive intake that is mediated by positive and
negative reinforcement, respectively. Once a person transitions to compulsive
drug use, negative reinforcement mechanisms play a substantial role in
continued, escalated drug use. Negative reinforcement is a behavioral
mechanism whereby greater drug taking is strengthened by the alleviation of a
negative emotional state that is precipitated by absence of the drug. In recent
years, attention has focused on understanding the neurobiological mechanisms,
including specific neuroadaptations that underlie this negative emotional state
that is produced by drug withdrawal and abstinence because of its central role in
relapse. Neuroadaptations in the brain reward, executive, and stress systems are
key drivers of the compulsion to continue drug intake despite adverse
consequences. Decreases in DA and GABA in the ventral striatum (where NAc
is located) are coupled with the recruitment of brain stress systems in the
extended amygdala and habenula, which in turn inhibit DA cell firing and DA
release (42). The extended amygdala is a composite structure that comprises the
central nucleus of the amygdala (CeA), the bed nucleus of the stria terminalis
(BNST), and a transition area in the medial and caudal portions of the NAc (43).
A key player in the brain stress systems is dysregulation of the hypothalamic–
pituitary–adrenal (HPA) axis and the recruitment of extrahypothalamic
corticotropin-releasing factor (CRF) in the extended amygdala (44). In animal
models, CRF receptor antagonists blocked alcohol self-administration in
dependent rats during both acute withdrawal and protracted abstinence and also
blunted compulsive-like responding for all major drugs of abuse, and many of
these effects have been localized to the extended amygdala (44). Withdrawal
from all addictive drugs that have been studied to date leads to an activated HPA
stress response. However, repeated withdrawal and the repeated activation of
glucocorticoids (effectors of the HPA axis) can lead to a blunted HPA stress
response along with sensitization of the CRF–CRF1 receptor systems of the
extended amygdala, causally linking the neuroendocrine and extrahypothalamic
CRF system stress responses in the development of addiction (44).
Consistent with a functional role for the HPA axis component of the
opponent process, glucocorticoid receptor antagonists reduced the development
and expression of excessive alcohol self-administration that resulted from
repeated, intermittent alcohol intoxication (45) and alcohol seeking in a human
laboratory study (46).The excessive release of DA and opioid peptides produces
the subsequent activation of dynorphin systems, which through their activation
of κ opioid receptors decreases DA release. A decrease in DA release contributes
to the dysphoria that is associated with addiction (47) and more generally to
negative emotional states (48). Indeed, κ opioid receptor antagonists block the
depression-like, aversive responses to stress, and dysphoric-like responses
during drug withdrawal and compulsive-like responding in animal models (49).
Additionally there is evidence that norepinephrine, vasopressin, substance P,
hypocretin (orexin), and inflammatory cytokines also contribute to negative
emotional states of drug withdrawal, which are most prominent for alcohol and
opioids (50). Recruitment of the brain stress systems in the extended amygdala is
also accompanied by compensatory mechanisms that oppose these effects. Such
“buffer systems” include neuropeptide Y (NPY), nociceptin, and the
endocannabinoid system, which act to restore homeostasis to extended amygdala
circuits and modulate stress responses (51,52). Thus, one can envision stress
system recruitment (the overactivation of CRF or dynorphin-κ opioid receptors)
or buffer system failure (low activation of NPY, nociceptin, or
endocannabinoids) that contributes to vulnerability, severity, and relapse in
addiction under the conceptual framework that is conveyed by negative
reinforcement. In human imaging studies, hyperactivity of the amygdala,
thalamus, and hippocampus and a decrease in amygdala connectivity with the
anterior cingulate gyrus were observed in response to angry and fearful facial
expressions in people with a current cocaine use disorder compared with
controls (Fig. 1-6 (54)). Increases in amygdala activation were also
independently associated with an earlier age of first cocaine use and longer
exposure to cocaine (54).
Figure 1-6. Neuroimaging showing sensitization of amygdala

during fear responses (withdrawal–negative affect stage).
Brain image of a cocaine-dependent individual showing
significantly increased activation in the left amygdala in
response to fearful and angry faces during an emotional face-
matching task. Amygdala activity and amygdala connectivity
during the emotional face-matching task, known to activate
the amygdala (Morris JS, et al. A neuromodulatory role for
the human amygdala in processing emotional facial
expressions. Brain. 1998;121(Pt 1):47-57. Ref. (53)) were
assessed in 51 cocaine-using males and 32 non–drug-using
healthy males using functional magnetic resonance imaging
(fMRI). Male healthy non–drug-using controls and male
current cocaine users, 22-50 years old, were included when
using at least 1 g of cocaine during at least two occasions per
week for the last 6 consecutive months. (Crunelle CL, et al.
Dysfunctional amygdala activation and connectivity with the
prefrontal cortex in current cocaine users. Hum Brain Mapp.
2015;36:4222-4230.)
There is also evidence of impairments in ancillary circuits that are likely to

contribute to compulsive-like behaviors that are seen in individuals with
addiction. For example, insular dysfunction can affect the ability to properly
evaluate internal states (55), and impairments in the lateral habenula can
compromise the ability to properly process and learn from disappointments and
might disrupt mood (56). Finally, in addition to classic neurotransmitter systems,
recent studies link neuroinflammatory signaling in the brain to drug use and
addiction. For example, central immune signaling activation is associated with
the abuse of alcohol, opioids, cocaine, and methamphetamine (57). Alterations
of neuroimmune signaling regulate alcohol drinking behavior and may
contribute to negative affect and depression-like behaviors that are induced by
alcohol (58,59) and opioids (60,61) and additionally contribute to the toxicity
associated with alcohol (62) and other drugs, such as methamphetamine and
opioids (63,64).
NEUROBIOLOGY OF DRUG
ADDICTION: PREOCCUPATION–
ANTICIPATION (“CRAVING”) STAGE
A hallmark of addiction involves poor inhibitory control and poor executive
function, which are mediated by prefrontal cortical regions in the brain. For
example, regions of the PFC are selectively damaged by chronic intermittent
drug use (alcohol, cocaine, marijuana) use and result in poor decision-making
that can perpetuate the addiction cycle. Indeed, gray matter volume deficits in
specific medial frontal and posterior parietal–occipital brain regions are
predictive of relapse risk, suggesting a significant role for gray matter atrophy in
poor clinical outcomes in alcoholism (see Fig. 1-7 (65)). Similar, although not
identical, findings have been observed for opioid, cocaine, and cannabis use
disorders (66–69). Adaptations also appear to occur in regions that are
innervated by mesolimbic DA circuits (including the NAc, amygdala,
hippocampus, and PFC), which may contribute to greater salience of the drug
and drug stimuli and the lower sensitivity to natural reinforcers (7). Whether
tested during early or protracted withdrawal, individuals with addiction present
lower levels of DA D2 receptors in the striatum (including the NAc), which are
associated with decreases in the baseline activity of frontal brain regions that are
implicated in salience attribution (orbitofrontal cortex [OFC]), inhibitory control,
and error monitoring (anterior cingulate gyrus [ACC]), the disruption of which
results in compulsivity and impulsivity (70). These results point to an imbalance
between dopaminergic circuits that underlie reward and conditioning and those
that underlie executive function (emotional control and decision-making). We
postulate that this imbalance contributes to compulsive drug use and the loss of
control in addiction. For example, increases in DA are likely to play a role in
error prediction that is important for stimulus–reward learning (71) and the
assignment of salience (35). Salience refers to stimuli or environmental changes
that are arousing or that elicit an attentional–behavioral switch (72). Salience,
which applies not only to reward but also to aversive, new, or unexpected
stimuli, affects the motivation to seek the anticipated reward and facilitates
conditioned learning and engages DA D1 receptors (73,74). This provides a
different perspective about drugs because it implies that drug-induced increases
in DA will inherently motivate further procurement of more drug (regardless of
whether the effects of the drug are consciously perceived to be pleasurable).
Indeed, some addicted individuals report that they seek the drug even though its
effects are no longer pleasurable. Drug-induced increases in DA through D1
receptor stimulation will also facilitate conditioned learning, in which previously
neutral stimuli that are associated with the drug become salient. These
previously neutral stimuli then increase DA by themselves and elicit the desire
for the drug (75). This may explain why the person with addiction is at risk of
relapse when exposed to an environment where he previously administered the
drug.
Figure 1-7. Neuroimaging showing decreased frontal activity
correlated with relapse vulnerability (preoccupation–
anticipation stage), with significant clusters of gray matter
volume deficit in alcohol-dependent patients relative to
healthy comparison subjects. Panel A presents estimated
survival risk functions (with mean age, IQ, and baseline total
amount of alcohol consumed held constant) for mean gray
matter volumes as well as for volumes one and two standard
deviations above and below the mean for the medial frontal
cluster (cluster χ2 = 6.7, p < 0.009; hazard ratio = 0.52, 95%
CI = 0.31-0.85). Although the survival function was a 90-day
analysis, the graphs are cut off at day 60 because all alcohol-
dependent patients with gray matter volumes two standard
deviations below the mean for each of the two regions
relapsed by day 60. For patients with volumes two standard
deviations above the mean in the medial frontal cluster, the
estimated survival function at day 60 spans a 0.68 (68%)
proportion of surviving relapse, whereas for patients with
volumes two standard deviations below the mean, the
estimated survival function at day 60 for both regions spans
only a 0.02% chance of surviving relapse. Panel B shows the
right lateral prefrontal cortex with crosshairs at Montreal
Neurological Institute (MNI) coordinates x = 51, y = 40, z =
19 (Brodmann area 46; dorsolateral prefrontal cortex). (Taken
from Rando K, et al. Association of frontal and posterior
cortical gray matter volume with time to alcohol relapse: a
prospective study. Am J Psychiatry. 2011;168:183-192, with
permission.)
At the neurotransmitter level, addiction-related adaptations have been reported

not only for DA but also for glutamate, GABA, opioids, serotonin, cannabinoids,
and various neuropeptides (76). These changes contribute to the abnormal
function of brain circuits. For example, in individuals who are addicted to
cocaine, imaging studies have shown that disruptions of DA activity in the brain
(reflected by reductions of D2 receptors in the striatum and reductions of DA
release) (77) are associated with lower baseline activity in the OFC and anterior
CG (brain regions that are involved in salience attribution and inhibitory control
(70); Fig. 1-8). Abnormal function of these cortical regions has been particularly
revealing in furthering our understanding of addiction because their disruption is
linked to compulsive behavior (OFC) and disinhibition (CG) (70). The combined
research of the last decade reveals that drug-induced impairments in areas of the
PFC exert a twofold greater impact on addiction, first through its perturbed
regulation of limbic reward regions and second through its involvement in
higher-order executive function (eg, self-control, salience attribution, and
awareness) (79). Therefore, abnormalities in these PFC regions could underlie
both the compulsive nature of drug administration in individuals with addiction
and their inability to control their urges to take the drug when they are exposed
to it (80). They are also likely to contribute to the impaired judgment and
cognitive deficits that are seen in many people with addiction. Additionally,
animal studies have shown that drug-related adaptations in these PFC regions
result in greater activity of the glutamatergic pathway that regulates DA release
in the NAc (81). Adaptations in this pathway appear to play a role in the relapse
that occurs after drug withdrawal in animals that are previously trained to self-
administer a drug when they are again exposed to the drug, a drug-related
stimulus, or stress (81). Moreover, brain imaging studies have shown that the
more that individuals with a cocaine use disorder can engage the PFC, the more
they can inhibit activation of the NAc that follows exposure to cocaine-related
cues (82).
Figure 1-8. Dopamine D2 receptors and glucose metabolism
in addiction. A, B: Positron emission tomography (PET)
images showing DA D2 receptors and brain glucose
metabolism in the OFC (orbitofrontal cortex) in controls (A)
and in individuals who use cocaine (B). Note that the
individuals using cocaine have reductions in both D2
receptors and in OFC metabolism. C: Correlation between
measures of D2 receptors and brain glucose metabolism in
the OFC and anterior cingulate gyrus (CG) of both cocaine
and methamphetamine users. The lower the D2-receptor
expression, the lower the metabolism in the OFC and CG.
Decreased activity in the OFC, a brain region that is
implicated in salience attribution and whose disruption results
in compulsive behavior, could underlie the compulsive drug
administration that occurs in addiction. Decreased activity in
the CG, a brain region that is involved in inhibitory control,
could underlie the inability to restrain from taking the drug
when the addicted person is exposed to it. (Volkow ND,
Fowler JS, Wang GJ, et al. Dopamine in drug abuse and
addiction: results of imaging studies and treatment
implications. Arch Neurol.. 2007;64:1575-1579. Ref. (78).)
At the molecular-cellular level, drugs have been reported to alter the expression
of certain transcription factors (nuclear proteins that bind to regulatory regions
of genes, thereby regulating their transcription into mRNA), and a wide variety
of proteins that are involved in neurotransmission in several key brain regions.
Growing evidence suggests that epigenetic mechanisms mediate many drug-
induced changes in gene expression patterns that lead to structural, synaptic, and
behavioral plasticity in the brain (83). The dynamic and often long-lasting
changes that occur in the transcription factors ΔFosB, cAMP-responsive
element-binding protein (CREB), and nuclear factor κB after chronic drug
administration are particularly interesting because they appear to modulate the
synthesis of proteins that are involved in key aspects of the addiction phenotype,
such as synaptic plasticity (84). Indeed, chronic drug exposure can alter the
morphology of neurons in DA-regulated circuits. For example, in rodents,
chronic cocaine, alcohol, or amphetamine administration alters neuronal
dendritic branching and spine density in the NAc and PFC. This adaptation is
thought to play a role in the greater incentive motivational value of the drug in
addiction (85–87). These molecular changes can influence all three stages of the
addiction cycle, thereby loading the circuits that contribute to neuroadaptations
in reward-motivation, stress-emotion, executive function-self regulation, and
interoceptive-self awareness networks in the brain whose dysfunction coalesce
to drive compulsive alcohol and drug intake.
VULNERABILITY TO ADDICTION
Genetic Factors
It is estimated that 40-60% of the vulnerability to addiction is attributable to
genetic factors (88). In animal studies, several genes have been identified that
are involved in drug responses, and their experimental modifications markedly
affect drug self-administration (89). Animal studies have identified candidate
genes and genetic loci for alcohol responses that overlap with genes and loci that
are identified in human studies (90,91). For example, genes on mouse
chromosome 1 and human chromosome 1q are associated with alcohol
withdrawal responses. Genome-wide association studies (GWASs), which
interrogate all of the common genetic variants for correlations with alcohol
phenotypes, have proven to be a useful approach to identify novel variants (92).
A GWAS of alcohol consumption identified the autism susceptibility candidate 2
(AUTS2) gene in a large population-based sample (93). A family-based GWAS
of frontal theta oscillations, an endophenotype of alcoholism, found that the
potassium channel gene KCNJ6 was responsible for a significant amount of
variations in that measure (94). Progress in identifying candidate genes for
alcoholism and alcohol-related responses continues at a rapid pace (95).
However, identifying the biological function of these new candidate genes will
be a major challenge in the next decade. The hope is that a better understanding
of the myriad interacting genetic factors and networks that influence addiction
risk and trajectory will help increase the efficacy of addiction treatments and
reduce the likelihood of relapse (96). A prime example of a successful move
from gene identification to biological function is the association between drug-
metabolizing genes and protection against alcohol use disorder. Some of these
polymorphisms interfere with drug metabolism, influencing the amount of time a
drug circulates through the body. For example, specific alleles of the genes that
encode alcohol dehydrogenases ADH1B and ALDH2 (enzymes that are
involved in the metabolism of alcohol) are reportedly protective against
alcoholism (97). Similarly, polymorphisms in the gene that encodes cytochrome
P-450 2A6 (an enzyme that is involved in nicotine metabolism) are reportedly
protective against nicotine addiction (98). Furthermore, genetic polymorphisms
in the cytochrome P-450 2D6 gene (an enzyme that is involved in the conversion
of codeine to morphine) appear to provide a degree of protection against the
nonmedical use of codeine (99). These polymorphisms of drug-metabolizing
genes operate by modulating the accumulation of toxic metabolites that are
aversive; therefore, if alcohol or drugs are consumed by individuals who carry
variants that convert their substrate at high rates, then the accumulation of toxic
metabolites serves as a negative stimulus to prevent further consumption.
Some polymorphisms of receptor genes that mediate effects of drug have
also been associated with a higher risk of addiction. For example, a number of
convergent results support a CHRNA5/CHRNA3/CHRNB4 gene cluster
association with nicotine dependence (100–103) and the risk of such smoking-
related diseases as lung cancer and peripheral arterial disease (104). Similarly,
polymorphisms of the MOR gene have been associated with a higher risk for an
opioid or alcohol use disorder (105,106). Associations have also been found
between alcohol dependence and the genes that encode GABAA (GABRG3 (107)
and GABRA2 (108)). Particularly interesting in this context are findings related
to the association between DRD4 variable number tandem repeat polymorphisms
and attention-deficit/hyperactivity disorder (ADHD), personality traits that
influence risk taking, addiction, and addiction-related phenotypes (109). The
likely involvement of DRD4 in addiction trajectories is potentially very
important in light of its alleged ability to moderate the impact of environments
on behavior and health (110). The replication of many of the genetic findings in
SUDs is still pending, but such techniques as exome sequencing (where one
sequences all of the protein-coding regions of the genome) will identify variants
that may play a direct role in altering the function of the corresponding protein.
Environmental Factors
Environmental factors that have been consistently associated with a propensity
to drug use include low socioeconomic class, poor parental support, within–peer
group deviancy, and drug availability, all of which contribute to stress, which
may be a common feature of a wide variety of environmental factors that
increase the risk for drug use. The mechanisms that are responsible for stress-
induced increases in vulnerability to drug use and relapse in people who are
addicted are not yet well understood. However, there is strong evidence that
dysregulation of stress-responsive CRF, vasopressin, dynorphin, hypocretin,
norepinephrine, and neuroinflammatory systems may contribute to a variety of
psychiatric disorders and SUDs (111), likely through their effects on the HPA
axis, extended amygdala, and other stress-responsive regions, such as the insula
and habenula (112) (see Withdrawal-Negative Affect Stage section above). A
recent study showed that social isolation during a critical period of adolescence
increases the vulnerability to addiction (113). Social isolation in adolescence
also increases anxiety and alcohol intake (114).
Imaging techniques now allow us to investigate the ways in which
environmental factors affect the brain and the ways in which these affect
behavioral responses to addictive drugs. For example, in nonhuman primates,
social status affects D2 receptor expression in the brain, which in turn affects the
propensity for cocaine self-administration in males (115) but not females (116).
Animals (males and females) that achieve a dominant status in the group show
greater numbers of D2 receptors in the striatum and are reluctant to administer
cocaine (males only), whereas animals that are subordinate have fewer D2
receptors and readily administer cocaine. Because studies in male rodents have
shown that increasing D2 receptors in the NAc markedly decreases drug
consumption (which has been shown for alcohol and cocaine) (117,118), this
could provide a mechanism by which a social stressor can modify the propensity
to self-administer drugs, at least for males. These results also highlight the need
to understand potential gender differences in the neurobiological responses of
the brain to stressors and their subsequent contribution to drug taking.
Long-lasting changes in gene expression that are induced by environmental
events, such as drug or alcohol exposure, are now being studied as a means to
identify the ways in which the environment can contribute to drug and alcohol
addiction. These long-lasting changes in gene expression are mediated by
epigenetic mechanisms, including DNA methylation, histone modification, and
microRNAs. For example, the acute anxiolytic effects of alcohol in rats were
associated with a decrease in histone deacetylase (HDAC) activity and an
increase in the acetylation of histones H3 and H4. CREB-binding protein (CBP)
and NPY expression levels increased in the amygdala, a major brain region that
is implicated in stress and anxiety.
Conversely, anxiety-like behaviors during withdrawal after chronic alcohol
exposure were highly correlated with an increase in HDAC activity and
decreases in the acetylation of H3 and H4 and levels of CBP and NPY in the
amygdala (85). Treatment with the HDAC inhibitor trichostatin A in rats
reversed the deficits in H3, H4, and NPY expression and prevented the
development of alcohol withdrawal–related anxiety in the elevated plus maze
and light/dark box test. Based on the effect of trichostatin A, the authors
suggested the possibility that neuroadaptations in the amygdala during chronic
alcohol exposure may involve both histone acetyltransferases and HDACs in the
dynamic process of chromatin remodeling (119).
An increasingly relevant example of an environmental factor that negatively
impacts brains that are hardwired to respond and seek immediate rewards can be
found in the ubiquitous availability of high-calorie “junk” food, which can hijack
deeply entrenched (evolved) homeostatic mechanisms to easily override
inhibitory controls in vulnerable individuals and facilitate behaviors that lead to
obesity (38). A similarly deleterious relationship between greater availability and
negative impacts on health can also be found in the more widespread nonmedical
use of stimulant (eg, ADHD) medications (120,121), high rates of opioid
analgesic prescriptions and overdose deaths (122,123), and the steady increase in
marijuana use among young people (124).
Comorbidity with Mental Illness

The risk for a SUD in individuals with mental illness is significantly higher than
for the general population (125). The high comorbidity probably reflects, in part,
overlapping environmental, genetic, and neurobiological factors that influence
drug use and mental illness (126–128).
Alcohol use disorder also often presents in combination with the use of other
drugs and psychiatric disorders, including mood, anxiety, sleep, and psychotic
disorders. Among individuals with alcohol use disorder, nearly 40% have at least
one lifetime psychiatric diagnosis and more than 20% have another SUD.
Similarly, individuals with a mood disorder are at increased risk for an opioid
use disorder, which in turn increases their risk for overdose fatalities and
suicidality (129), Almost 30% of people with psychiatric disorders present with
a SUD, and 25% have an alcohol use disorder and 15% have another drug use
disorder. These comorbidities are problematic because they can complicate
treatment and lead to synergistic negative effects on health that are worse than
any of the disorders alone. For example, depression can deplete patients of the
motivation that is required to maintain recovery from alcohol. Depressed
individuals with alcohol use disorder have 59% more severe suicidal symptoms
compared with depressed nondependent individuals, and depression is predictive
of relapse to drinking.
It is likely that different neurobiological factors are involved in comorbidity,
depending on the temporal course of its development (ie, mental illness followed
by drug use or vice versa). In some instances, the mental illness and addiction
appear to co-occur independently (130). In others, there might be sequential
dependency. It has been proposed that comorbidity might be attributable to use
of the drugs to self-medicate the mental illness in cases in which the onset of
mental illness is followed by the use of some types of drug. When drug use is
followed by mental illness, chronic excessive drug exposure could lead to
neurobiological changes, which might explain the greater risk of mental illness
(131). For example, the high prevalence of smoking that is initiated after
individuals experience depression could at least partially reflect the
antidepressant effects of nicotine and the antidepressant effects of monoamine
oxidase A and B inhibition by cigarette smoke (132). The reported risk for
depression with early drug use (133) could reflect neuroadaptations of the DA
systems and the recruitment of brain stress systems that might make individuals
more vulnerable to depression. Also in this category are the multiple
observations that suggest that cannabis exposure may be a “component cause”
that, in combination with other factors (eg, preexisting/genetic vulnerabilities),
could contribute to schizophrenia or other psychotic disorders (134).
The higher risk of drug use in individuals with mental illness highlights the
relevance of the early evaluation and treatment of mental diseases as an effective
strategy to prevent drug addiction that starts as self-medication.
STRATEGIES TO COMBAT ADDICTION

Knowledge of the neurobiology of drugs and the adaptive changes that occur
with SUDs is guiding new strategies for prevention and treatment and
identifying areas in which further research is required.
Preventing Addiction
The greater vulnerability of adolescents to experimentation with addictive drugs
and to subsequent addiction underscores why the prevention of early exposure is
such an important strategy to combat drug addiction. Epidemiological studies
show that the prevalence of drug use in adolescents has changed significantly
over the past 30 years, and some of the decreases appear to be related to
education about the risks of drugs, but some of the increases may be related to
changes in the perception of such risks. For example, for marijuana, the
prevalence rates of use in the United States in 1979 were as high as 50%. In
1992, they were as low as 20% (135) (Fig. 1-9) but now have increased
significantly among 18-25 year olds, although these rates have remained stable
among adolescents. Interestingly, in contrast to the stable levels of marijuana use
among teenagers, the use of other drugs, both legal (alcohol and nicotine) and
illegal (cocaine, methamphetamine, heroin, ecstasy, and inhalants), and
prescription medications (stimulants, opioids, benzodiazepines) has continued to
decrease in the United States (136). Moreover, in the past, we had observed a
strong relationship between perception of the risks that are associated with
marijuana consumption and its use. When adolescents perceived the drug to be
risky, the rate of use was low, whereas when they did not, the rate of use was
high. This is no longer the case. Despite the significant decreases over the past 5
years in the perception of marijuana as risky, its use has not changed during this
time period (136). Some of the significant decreases in ecstasy use and cigarette
smoking in adolescents (135) reflect effective prevention campaigns, which
provide evidence that, despite the fact that adolescents are more likely to take
risks, interventions that educate them about the harmful effects of drugs through
age-appropriate messages can decrease the rate of drug use (137–139).
Nevertheless, there is evidence that despite the decrease in alcohol use, there has
been a dramatic increase in high-intensity drinking (defined as 10-15 drinks in a
given setting) in the United States, as shown by steady increases in emergency
room visits that are linked to alcohol in the last 8 years (140). Thus, not all
media campaigns and school-based educational programs have been successful
in preventing hazardous or unhealthy substance use (141,142). Tailored
interventions that take into account socioeconomic, cultural, and age and gender
characteristics of children and adolescents are more likely to improve the
effectiveness of the interventions.
Figure 1-9. Use and risk perception of marijuana. The
prevalence rate for marijuana use in the past 12 months and
the perception of marijuana as a dangerous drug in 12th
graders (18-19 years old) between 1975 and 2012. When
teenagers perceived marijuana as dangerous, the prevalence
of drug use was low and vice versa. (From Johnston LD,
O'Malley PM, Bachman JG, et al. Monitoring the Future
National Survey Results on Drug Use. 2012 Overview.
Publication No. 07-6205. Bethesda, MD: National Institutes
of Health, 2012.)
Currently, prevention strategies include not only educational interventions that

are based on comprehensive school-based programs and effective media
campaigns and strategies that decrease access to drugs and alcohol but also
strategies that provide supportive community activities that engage adolescents
in productive and creative ways. However, as we begin to understand the
neurobiological consequences that underlie the adverse environmental factors
that increase the risks for drug use and addiction, we will be able to develop
interventions to counteract these changes. As we deepen our knowledge of the
ways in which different genes (and their encoded proteins) make a person more
or less vulnerable to taking drugs and addiction, more targets will be available to
tailor interventions for those at higher risk.
Finally, we can also expect a renewed focus in the near future in the research
and development of interventions that increase general resilience that leads to
universally better outcomes. Particularly promising in this context are the recent
results of a major longitudinal study that showed a dramatic positive influence of
childhood self-control on a wide range of life outcomes, including substance use
risk, overall health, and financial status (143). Future studies are needed to
investigate whether there are other factors that also contribute to the significant
reduction of the consumption of alcohol and other drugs among adolescents in
the United States (ie, some [prosocial] forms of interactions among teenagers
through social media rather than in physical venues that favor peer pressure for
drug consumption, alternative sources of rewarding behaviors such as some
video games).
Treating Addiction
The adaptations in the brain that result from chronic drug exposure are long
lasting; therefore, addiction must be viewed as a chronic disease (51). This is
why long-term treatment will be required for most people with addiction, just as
it is for other chronic diseases, like hypertension, diabetes, or asthma (144). By
recognizing the likelihood of relapse, this perspective radically modifies our
expectations of addiction treatment outcomes, establishing the need for a more
rational, chronic management model for addiction treatment (145). The
discontinuation of treatment, as for other chronic diseases, is likely to result in
relapse. As for other chronic medical conditions, relapse should not be
interpreted as a failure of treatment (as is the prevailing view for most people
who are diagnosed with addiction), but instead as a temporary setback due to a
lack of compliance or tolerance to an effective treatment (144). It is rather telling
that the rates of relapse and recovery in the treatment of drug addiction are
equivalent to those of other medical diseases (144).
The involvement of multiple brain circuits (reward, motivation, memory,
learning, stress, emotion, interoception, inhibitory control, and executive
function) and the associated behavioral disruptions point to the need for a
multimodal approach to the treatment of addiction. Therefore, interventions
should not be limited to inhibiting the rewarding effects of a drug—they should
include strategies to enhance the salience of natural reinforcers (including social
support), strengthen inhibitory control, decrease conditioned responses, improve
mood, reduce stress, and strengthen executive function and decision-making.
Among the recommended multimodal approaches, the most obvious rely on
the combination of pharmacological and behavioral interventions, which might
target different underlying factors and thus have synergistic effects. Such
combined treatments are strongly recommended because behavioral and
pharmacological treatments are thought to operate through different yet
complementary mechanisms that can have additive or even synergistic effects.
Thus, it could be expected that addiction treatments that use behavioral
interventions would be more effective when complemented with medications to
help the patient remain drug-free. For example, behavioral approaches
complement most tobacco addiction treatment programs. They can amplify the
effects of medications by teaching people how to manage stress, recognize and
avoid high-risk situations for smoking relapse, and develop alternative coping
strategies (eg, cigarette refusal skills, assertiveness, and time management skills)
that they can practice in treatment, social, and work settings (146,147).
Pharmacological Interventions
Pharmacological interventions can be grouped into two classes. First, there are
those that interfere with the reinforcing effects of addictive drugs (ie,
medications that interfere with binding to a target, drug-induced DA increase,
postsynaptic responses, or the drug’s delivery to the brain, like antidrug
antibodies or medications that trigger aversive responses). Second, there are
those that compensate for the adaptations that either preceded or developed after
long-term use (ie, medications that decrease the prioritized motivational value of
the drug, enhance the salience of natural reinforcers, or interfere with
conditioned responses, stress-induced relapse, or motivational aspects of
withdrawal). The usefulness of some addiction medications has been clearly
validated; for others, the data are still preliminary. For these, most results are
limited to promising preclinical findings. Table 1-1 summarizes U.S. Food and
Drug Administration (FDA) approved medications and medications for which
there are preliminary clinical/preclinical data. Many of these promising new
medications target different neurotransmitters (such as GABA, serotonin, or
glutamate) relative to older drugs, offering a wider range of therapeutic options.
Combining medications may increase their efficacy, as recently shown for a
tobacco (nicotine) use disorder treatment (184).
TABLE 1-1 Medications for Treating Drug and Alcohol

Addiction
Medications used for physical withdrawal are not included.
aAntiepileptic drugs that have been shown to decrease drug-induced DA increases as well as conditioned
response.
FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GABAB, GABA type B; 5HT3, 5-
hydroxytryptamine (serotonin) receptor subtype 3; MAO-B, monoamine oxidase B.
Behavioral Interventions
In a similar fashion, behavioral interventions can be classified according to their
intended remedial function, such as to strengthen inhibitory control circuits,
provide alternative reinforcers, reduce stress, improve mood, or strengthen
executive function. Traditionally, behavioral therapy has focused on symptom-
based targets rather than underlying causes of addiction. However, for other
brain disorders, new views of brain plasticity that recognize the capacity of
neurons in the adult brain to increase synaptic connections and in certain
instances to regenerate (185) have resulted in more focused cognitive–behavioral
interventions that are designed to increase the efficiency of dysfunctional brain
circuits. This has been applied to attempts to improve reading in children with
learning disabilities (186), improve memory-related brain activity in Alzheimer’s
disease patients (187), strengthen voluntary cortical control in children with
ADHD (188), and facilitate motor and memory rehabilitation after brain injury
(88). We are beginning to see the first glimpses of this general approach as
potentially applicable to the treatment of drug addiction. For example, a small
positive relationship was found between cognitive-specific strategies, such as
using positive self-talk and a better ability to cope with the urge to smoke (189).
Similarly, a recent imaging study of people who used cocaine showed that
specific instructions to purposefully inhibit cue-induced craving were associated
with inhibition in the (limbic) NAc, insula, and orbitofrontal and cingulate
cortices and reduced cocaine craving (82). Dual approaches that pair cognitive–
behavioral strategies with medications to compensate for or counteract the
neurobiological changes that are induced by chronic drug exposure are also a
promising area of translational research that might, in the near future, provide
more robust and longer-lasting treatments for addiction than either when given in
isolation (190). A new and exciting area of research in this context is the
emerging area of translational research that focuses on understanding how and
why behavioral interventions work in terms of neurobiological function and
structure (191,192).
Treating Comorbidities
The use of multiple substances (eg, alcohol + nicotine or alcohol + cocaine)
should be considered in the proper management of individuals with addiction.
Similarly, comorbidities with other mental illnesses will require treatment for the
mental illness concurrent with treatment for drug use. Because addictive drugs
adversely affect many organs in the body (Fig. 1-10), they can contribute to the
burden of many medical diseases, including death from overdoses, cancer,
cardiovascular and pulmonary diseases, HIV/AIDS, and hepatitis C, as well as to
accidents and violence. Therefore, substance use treatment will help to prevent
or improve the outcome for many medical diseases. The HIV/AIDS epidemic
provides one of the best examples. Drug use and addiction have been fueling the
global spread of HIV from the very beginning of the AIDS epidemic. This
inextricable connection is predicated on at least three major threads: (a) the
direct effects of contaminated injection drug use on infection rates, (b) the
indirect impact of addictive drugs on high-risk sexual behaviors and treatment
adherence, and (c) the drugs’ ability to worsen neurological complications that
stem from HIV infection. Fortunately, recent research has now shown
conclusively that (a) HIV prevention among drug users (which includes HIV
treatment) is effective in reducing HIV prevalence and (b) treating SUDs
(particularly with the aid of new and more effective medications) improves HIV
treatment outcomes and should be parlayed into global instruments for severing
those threads once and for all. A particularly promising approach in this context
has emerged in the form of the Seek, Test, Treat, and Retain paradigm that seeks
out hard-to-reach/high-risk populations, including drug users and those in the
justice system, tests them for HIV, links those who test positive to HIV treatment
and other services, and provides the necessary support to ensure these
individuals remain in the care system (193,194). Similarly, the treatment of SUD
decreases the incidence of hepatitis C infection (195).
Figure 1-10. Monoamine oxidase B concentration and
cigarette smoking. Positron emission tomography (PET)
images of the concentration of the enzyme MAO-B
(monoamine oxidase B) in the body of a healthy control and
of a cigarette smoker. There are significant decreases in the
concentration of the enzyme throughout the body of the
smoker. (Reproduced from Fowler JS, Logan J, Wang GJ,
Volkow ND. Monoamine oxidase and cigarette smoking.
Neurotoxicology. 2003;24:75-82, with permission.)
CHALLENGES FOR SOCIETY

In most cases, SUD alienates individuals from both their families and
communities, increasing isolation and interfering with treatment and recovery.
Because both the family and the community provide integral aspects of effective
treatment and recovery, this identifies an important challenge: to reduce the
stigma of addiction that interferes with intervention and proper rehabilitation.
The effective treatment of drug addiction in many individuals requires the
consideration of social policy, such as the treatment of people with addiction in
the justice system, the role of unemployment in the vulnerability to drug use, and
family dysfunctions that contribute to stress and that might block the efficacy of
otherwise effective interventions. For example, studies have shown that
providing drug treatment to prisoners who had a SUD and continuing treatment
after they leave prison dramatically reduced not only their rate of relapse to drug
use but also their rate of reincarceration (196,197) and overdose (198–200).
Similarly, drug courts in the United States, which incorporate drug treatment into
the judicial system, have proved to be beneficial in decreasing drug use and
arrests of offenders who are involved in drug taking (201). However, despite
these preliminary positive results, there are many lingering challenges (202).
There are also many unanswered questions that future research should address.
For example, what are the active ingredients in the treatment of the drug
offender? How does the system address the fact that few offenders stay in
treatment long enough to receive the minimally required services? What are the
implications of these findings for pretrial diversion laws, postprison reentry
initiatives, and so on?
The recognition of addiction as a chronic disease that affects the brain is
essential for large-scale prevention and treatment programs that require
participation of the medical community. The engagement of primary care
physicians (internists, family physicians, pain specialists,
obstetricians/gynecologists, and pediatricians) and emergency medicine and
preventive medicine physicians will facilitate the early detection of drug use in
childhood and adolescence. A prerequisite for this will be the implementation of
adequate competencies and curricula in medical school education and
postgraduate residency training in addiction medicine. These models should be
replicated across all health professional training (nursing, physician assistants,
dental, pharmacy).
Moreover, screening for drug use could help clinicians better manage
medical diseases that are likely to be adversely affected by the concomitant use
of drugs, such as cardiac and pulmonary diseases. Unfortunately, physicians,
nurses, psychologists, and social workers receive little training in the
management of addiction, despite being one of the most common chronic
disorders, a situation that the National Institute on Drug Abuse and the National
Institute on Alcohol Abuse and Alcoholism are trying to address through the
development and deployment of such products as a Screening, Brief
Intervention, and Referral to Treatment (SBIRT) service program (203,204), as
well as a Web-based tutorial to train substance use healthcare providers.
Participation of the medical community in many countries, including the
United States, is further curtailed by the lack of reimbursement by most private
medical insurance policies for the evaluation or treatment of drug use and
addiction. This lack of reimbursement limits the treatment infrastructure and the
choices that the addicted person has with respect to their treatment. It also sends
a negative message to medical students who are interested in clinical practice,
discouraging them from choosing a specialty for which the reimbursement of
their services is limited by the lack of parity.
Another considerable obstacle in the treatment of addiction is the limited
involvement of the pharmaceutical industry in the development of new
medications. Such issues as stigmatization, the lack of reimbursement for drug
use treatment, and the perceived lack of a large market all contribute to the
limited involvement of the pharmaceutical industry in the development of
medications to treat drug addiction (205). The importance of this issue had been
identified by the Institute of Medicine of the United States, which recommended
in 1995 a program to provide incentives to the pharmaceutical industry as a way
of helping address this problem (206).
The translation of scientific findings in drug use into prevention and
treatment initiatives clearly requires partnerships with federal agencies, such as
the Substance Abuse and Mental Health Services Administration (which is
responsible for US programs to prevent and treat drug use) and the Office of
National Drug Control Policy (which is responsible for US programs to control
availability and reduce demand for addictive drugs). A good example of progress
in this area is the recent publication of the Surgeon General’s Report: Facing
Addiction: Alcohol Drugs and Health (U.S. Department of Health and Human
Services (HHS), Office of the Surgeon General, 2016). Furthermore,
improvements in prevention and treatment programs could result from
collaborations with other agencies and groups, such as the Department of
Education (which can bring prevention interventions into the school
environment), the Department of Justice (which can implement treatment
strategies that will minimize the chances of recidivism and reincarceration of
inmates with substance use problems), and state and local agencies (which can
bring evidence-based and science-based treatments into the communities).
As we learn more about the neurobiology of normal and pathological human
behavior, a challenge for society will be to harness this knowledge to effectively
guide public policy. For example, as we improve our understanding of the
neurobiological underpinnings of voluntary actions, how will society define the
boundaries of personal responsibility in those individuals who have impairments
in these very same brain circuits? The answer to this and other questions will
have implications not only for the management of drug offenders but also for
other offenders with such diagnoses as antisocial personality disorder and
conduct disorder. Critics of the medical model of addiction argue that this model
removes the responsibility of the addicted individual from his behavior.
However, the value of the medical model of addiction as a public policy guide is
not to excuse the behavior of the individual with a SUD but rather to provide a
framework to understand it and to treat it more effectively.
SUMMARY
Remarkable scientific advances have been made in the neurobiology of SUD in
the domains of genetics, molecular biology, behavioral neuropharmacology, and
brain imaging that offer critical new insights into the ways in which the human
brain engages in self-destructive compulsive drug seeking that characterizes
addiction and the ways in which the human brain engages executive and
motivational functional networks that allow us to optimize everyday decisions
and plan for the future. Drug addiction engages fundamental neurocircuits of
motivation in three stages: the basal ganglia in the binge–intoxication stage to
drive incentive salience and habits, the extended amygdala in the withdrawal–
negative affect stage to drive stress and negative emotional states, and the PFC
in the preoccupation–anticipation (“craving”) stage to drive executive
dysfunction, while at the same time enhancing the engagement of interoceptive
brain networks that make it difficult to ignore the craving and negative
emotional states that dominate the mental state of the addicted person.
However, the field is at a crossroads where major advances in understanding
the neurobiology of addiction have helped identify promising new medications
and improve behavioral treatments but where the translation of these findings
into clinical practice is limited by several factors, including the limited
involvement of the medical community in the treatment of addiction, the
restricted involvement of the pharmaceutical industry, the lack of reimbursement
by private insurance policies, and the stigma associated with drug addiction. One
of the main challenges for agencies like the National Institute on Drug Abuse
and the National Institute on Alcohol Abuse and Alcoholism is to develop and
disseminate knowledge that will help to overcome these obstacles (207).
ACKNOWLEDGMENTS
The authors thank M. Arends, R. Baler, M. Egli, R. Huebner, R. Litten, A.
Noronha, and M Reilly for thoughtful comments and editorial assistance. This
chapter has been adapted and updated from Volkow ND, Li TK. Drug addiction:
the neurobiology of behavior gone awry. Nat Rev Neurosci. 2004;5(12):963-970,
and Volkow ND and Warren, KR. Drug addiction: the neurobiology of behavior
gone awry. Principles of Addiction Medicine. 5th ed.
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adolescents in primary care: a literature review. Addict Behav. 2013;38:2146-2153.
205. Volkow ND, Skolnick P. New medications for substance use disorders: challenges and opportunities.
Neuropsychopharmacology. 2012;37: 290-292.
206. Fulco CE, Liverman CT, Earley LE, eds. Development of Medications for the Treatment of Opiate
and Cocaine Addictions: Issues for the Government and Private Sector (Institute of Medicine).
Washington, DC: National Academy Press, 1995.
207. U.S. Department of Health and Human Services, Office of the Surgeon General. Facing Addiction in
America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington DC: U.S.
Department of Health and Human Services, Office of the Surgeon General, 2016.
CHAPTER 2
Recommended Use of Terminology in
Addiction Medicine
Richard Saitz, Shannon C. Miller, David A. Fiellin and
Richard N. Rosenthal
CHAPTER OUTLINE
Introduction
Recommended Concepts and Terminology by Construct
Conclusions
INTRODUCTION
Addiction medicine specialists are uniquely positioned to be “change agents”
toward public health. Each should lead by example with the use of medically
clear, accurate, and nonstigmatizing terminology. Words reflect and impact the
way we think. Nowhere is this perhaps more evident than in the field of
addiction medicine. The terminology used in addiction medicine has
appropriately evolved with a changing understanding of the condition and
evolving attitudes. This is less a reflection of political correctness than it is a
response to a need for greater clarity and objectivity. Terminology used by
clinicians and researchers should be both scientifically accurate and
nonstigmatizing. This chapter serves only to introduce and briefly discuss key
issues in terminology, provide references for further exploration, and make
recommendations. It is not exhaustive in its coverage of all possible terms
related to addiction and its treatment.
The American Society of Addiction Medicine’s Journal of Addiction
Medicine and other leading journals have encouraged the use of precise
nonstigmatizing terminology (1–4). Furthermore, the International Society of
Addiction Journal Editors (ISAJE) published a recommendation statement
against the use of stigmatizing terms (5). The American Society of Addiction
Medicine has published policy statements on the issue of terminology (6,7).
Most recently, the U.S. Office of National Drug Control Policy posted a draft
statement on changing the language in our field (8).
RECOMMENDED CONCEPTS AND

TERMINOLOGY BY CONSTRUCT
Avoid Stigmatizing the Patient or the
Condition, and Seek Medically Defined
Terminology
Stigmatizing terms can negatively impact quality of care (9–11). For example,
research demonstrates that when patients are described as having substance
“abuse” instead of a “disorder,” clinicians are more likely to recommend
punitive approaches (9,10). While there may not be consensus on exactly which
terms in and of themselves are stigmatizing versus which are not, clearly using
terminology in a way that ignores the many human aspects of the patient beyond
their substance use and defines them by their behavior or condition is potentially
stigmatizing. Examples include the use of the terms “alcoholic,” “abuser,”
“drunk,” “user,” “addict,” or “junkie.” While some may view the use of age-old
terms such as “alcoholic” and “addict” as acceptable in 12-step or other
nonmedical settings, these terms could easily be replaced with more medically
defined and less stigmatizing terms that incorporate person-first language (eg,
patient with “alcohol use disorder” and not “alcoholic,” etc.). Our patients are
people first, who secondarily have a disease or disorder; using proper
terminology can remind clinicians, families, and patients of that fact.
The Spectrum of Use

Several terms are preferred when discussing the spectrum of unhealthy alcohol
and other drug use (12). Much of this section appears in an ASAM policy
statement (6).
1. Low- or lower-risk use (and nonuse)

2. Unhealthy (alcohol, other drugs) use
a. Hazardous use (13,14) or at-risk use
b. Harmful use
c. Addiction and substance use disorder
3. Low-risk use (or lower risk) or no use refers to consumption of an amount
of alcohol or other drugs below the amount identified as physically
hazardous and use in circumstances not defined as psychosocially
hazardous. This amount could be any (even a small) amount and is
empirically derived for each substance.
4. “Unhealthy” covers the entire spectrum including all use related to health
consequences including addiction. Unhealthy alcohol and other drug
(substance) use is any use that increases the risk or likelihood for health
consequences (hazardous use) or has already led to health consequences
(harmful use). Unhealthy use is an umbrella term that encompasses all
levels of use relevant to health, from at-risk use through addiction.
Unhealthy use is a useful descriptive term referring to all the conditions or
states that should be targets of preventive activities or interventions.
The exact threshold for unhealthy use is a clinical and/or public health decision
based on epidemiological evidence for measurably increased risks for the
occurrence of use-related injury, illness, or other health consequences. The term
“unhealthy” (just as with the descriptors “unsafe” or “hazardous” or “harmful”
or “misuse”) does not imply the existence of “healthy” or “safe” or
“nonhazardous” or “harmless” use or that there is a way to use the substances
properly (ie, without “misuse”).
a. Hazardous or at-risk use is use that increases the risk for health
consequences. These terms refer only to use that increases the risk or
likelihood of health consequences. They do not include use that has
already led to health consequences. Thresholds are defined by the
amount and frequency of use and/or by circumstances of use. Some of
these thresholds are substance specific and others are not. For example,
use of a substance that impairs coordination, cognition, or reaction time
while driving or operating heavy machinery is hazardous. Nonmedical
use or use in doses more than what is prescribed of prescription drugs
can be hazardous. Use of substances that interact (eg, two medications
with sedative effects like benzodiazepines and opioids) is hazardous.
Use of substances contraindicated by medical conditions is hazardous
(eg, alcohol use and hepatitis C virus infection or alcohol use and
postgastrectomy states). Any cocaine use can increase risk for
myocardial infarction; one-time use of hydrocarbon inhalants can lead
to sudden cardiac death; no known level of tobacco use is considered
risk-free; any alcohol or nicotine use during pregnancy is hazardous;
any use by youth likely increases risk for later consequences; use of any
potentially addictive substance is more hazardous for persons with a
family history or genetic predisposition to addiction than it is to those at
average risk in the general population. Alcohol is a known carcinogen,
so there is likely no use that is completely risk-free. On the other hand,
there are thresholds at which the risk increases for alcohol, and these
hazardous or at-risk amounts have been specified (12). The exact
definitions may change with evolving epidemiological evidence and can
also vary by preferences of those making clinical or public health
decisions regarding thresholds. In addition, individual factors beyond
age, sex, and other characteristics can affect risk (eg, weight), and
thresholds are not individualized; although they are useful guides
clinically, they cannot be thought of as absolute. For example, it is not
the case that drinking just under the threshold is associated with no risk
or that drinking just above the threshold confers a substantially greater
risk. Finally, some drugs (including alcohol) may have beneficial effects
(just like medications have risks and benefits), and these may accrue to
different conditions (eg, possible benefits for pain or heart disease, risks
for cancer).
b. Harmful substance use is the use that has resulted in health
consequences. The ICD-10 definition of harmful use can be
summarized as repeated use that has caused physical or mental damage
(15). Hazardous and harmful are mutually exclusive of each other.
These terms apply also to prescription (and nonprescription or over-the-
counter medications). The terms could also apply to potentially
addictive behaviors.
c. See “The Disease” below.
The WHO lexicon defines misuse as use for a purpose not consistent with legal
or medical guidelines (16). However, “misuse” is also a term used to describe
not taking (nonaddictive or others) medication as directed or missing doses (eg,
of an antihypertensive medication). The U.S. Department of Veterans Affairs
describes misuse as the target of alcohol screening and intervention, including
disorder and addiction (and labels that severe misuse). “Misuse” is not an
appropriate descriptor for “substance dependence,” “addiction,” or “substance
use disorder” because it minimizes the seriousness of the disorder (to “misuse”
the substance). “Misuse” also seems to have a value judgment at least potentially
implied, as if it were an accident, mistake, or alternatively purposeful (a choice),
neither of which would be appropriate for describing the varied states of
unhealthy use. As such, “misuse” can be seen as pejorative or stigmatizing.
“Problem” use is not preferred because it is not well-defined, used
sometimes to refer to harmful use but other times to encompass the spectrum,
and can lead to stigmatizing discussion (eg, “you have a problem” or “you are a
problem”). “Inappropriate” is not well-defined and carries a pejorative nuance.
“Binge or binge drinking” can be useful for public health messaging but needs to
be clearly defined as it is sometimes used to mean a heavy drinking episode but
also used to mean a several day long episode of heavy drinking or other drug use
(eg, cocaine). “Moderate” drinking (or use) is not preferred as a term because it
implies safety, restraint, avoidance of excess, and, even, health. Since alcohol is
a carcinogen and cancer risk appears at amounts lower than those generally
defined as hazardous, and lower limit amounts harmful to the fetus are not well-
defined, better terms for amounts lower than amounts defined as risky or
hazardous include “lower-risk” or “low-risk” amounts or simply the term
“alcohol use.”
The Disease
When referring to the disease, terms that have been defined and agreed upon
should be used. This specificity is essential in allowing clinicians to accurately
communicate with each other and researchers and policy makers to accurately
compare populations. Examples of terms that typically indicate a medical
disease and that are roughly synonymous include “addiction,” “substance use (or
gambling) disorder,” and “substance dependence.” “Addiction” is a term long
used by laypeople, patients, and healthcare providers to indicate a condition that
can be described as “characterized by an inability to consistently abstain,
impairment in behavioral control, craving, diminished recognition of significant
problems with one’s behaviors and interpersonal relationships, and a
dysfunctional emotional response” (7). However, the term “addicted” can be
problematic because it often incorrectly conflates addiction and physical
dependence.
In past decades, the American Psychiatric Association (APA) and the World
Health Organization International Classification of Diseases developed criteria
to provide a consensus definition of this disease known commonly as addiction
(15–18). We provide some historical context here.
The APA’s Diagnostic and Statistical Manual of Mental Disorders (DSM)
Committee on Substance-Related Disorders had “good agreement among
committee members as to the definition of the medical disease known as
addiction, but there was disagreement as to the label that should be used” (19).
“Addiction” was a consideration; however, there was concern that labeling it as
such could be pejorative and invite stigma. While there was agreement that the
term “addiction” would “convey the appropriate meaning of the compulsive
drug-taking condition and would distinguish it well from ‘physical’
dependence,” the concern for stigma resulted in changing the term from
“addiction” to (substance) “dependence.” Thus, “addiction” and “substance
dependence” were considered as synonymous and describing the same clinical
disease. In fact, a vote for (substance) “dependence” to be used and not
“addiction” was won by only one committee member vote.
Years later, the DSM’s committee chair as well as the directors of the
National Institute on Drug Abuse and National Institute on Alcohol Abuse and
Alcoholism published an editorial recognizing that the use of “substance
dependence” and not “addiction” as the label for this clinical disease was “a
serious mistake,” as “this has resulted in confusion among clinicians regarding
the difference between ‘dependence’ in a DSM sense, which is really ‘addiction,’
and (physical) ‘dependence’ as a normal physiological adaptation to repeated
dosing of a medication.” As such, they urged the APA to adopt the word
“addiction” for DSM-5.
With the publication of DSM-5 in 2013, the previous DSM terms “substance
abuse” and “substance dependence” were made obsolete (18). This was after
consistent findings from studies of over 200 000 study participants revealing that
these two terms “abuse” and “dependence” were clinically and statistically
recognized as representing a single disease with varying degrees of severity,
renamed in DSM-5 as “substance use disorder” with mild, moderate, or severe
severity ratings. Criteria for the disorder no longer included legal problems but
did (newly) include craving. In addition, rather than have the threshold as one or
more criteria (as in “substance abuse”) or three or more criteria (as in “substance
dependence”), the threshold was set at two or more criteria for “substance use
disorder” (20). Again, the Committee on Substance-Related Disorders chose
against using the term “addiction” to avoid possible stigma, even though
feedback to the committee from the College on Problems of Drug Dependence in
2009 and the Research Society on Alcoholism (2010) supported the use of the
term “addiction” (21).
“Substance use disorder” is well-defined (18), and the features of
“addiction” are carefully described (7). Each can be appropriately used if
referenced. The terms overlap and have similar meaning. However, DSM-5
criteria do not define “addiction.” The DSM-5 clarifies “addiction” was not
chosen as the label for substance use disorder, not only because of stigma but
also because of a desire to avoid conflict with the varied ways the construct is
used. While “addiction” is “in common usage in many countries to describe
severe problems” (not necessarily DSM criteria) “related to compulsive and
habitual use of substances,” and “some clinicians will choose to use the word
addiction to describe more extreme presentations” (18), p. 485 the DSM-5 does not
state that addiction should only be used to represent a “severe” substance use
disorder. The DSM-5 does not exclude addiction as present in a “moderate” or
“mild” substance use disorder, nor does a diagnosis of addiction require that six
(or more) criteria of a substance use disorder be present (O’Brien CP Chair,
DSM5 Substance-Related Disorders Committee. Personal Communication.
2016).
Finally, with respect to the term “dependence,” if this term is used, it should
be clearly defined as the ICD-10 disorder, as the DSM-IV disorder, or as
physical dependence, which does not necessarily indicate any disorder or
addiction and may simply reflect a pharmacological effect.
Treatment
Medication (including opioid agonist) treatment of addiction has been
mislabeled “drug,” “medication assisted,” “substitution,” or “replacement.”
These terms are inaccurate; their pejorative nature and their implicit
communication that pharmacotherapy is in some way inferior to psychosocial or
mutual help pathways to remission of substance use disorders may be partly
responsible for the slow uptake in practice of these efficacious treatments. These
treatments do not substitute for, reproduce the effects of, or replace illicit drugs.
And medications do not “assist” treatment, they are treatments shown to be
efficacious on their own, and studies often fail to show additional benefits of
added psychosocial therapies (22–26). More accurate alternatives would be
medication treatment, treatment, opioid agonist treatment, or even
psychosocially assisted pharmacotherapy (27). The jarring nature of the sound of
this last example (from a guide published by the World Health Organization
[WHO] in 2009) demonstrates how important language and terminology are in
shaping how patients and treatments are viewed. Describing patients as “using”
medications, rather than “taking” medications, reflects an even subtler stigma
that equates receipt of medications with drug use.
Also, during treatment, testing is often performed for addictive substances.
In these cases, results should be presented like other medical tests—“positive”
versus “negative” and “detected” versus “not detected”—and not “dirty” or
“clean,” which are then often used to describe people in a highly stigmatizing
way (“I am clean,” “your urine was dirty,” “I tested you today and you were
dirty”) (28).
CONCLUSIONS
This chapter does not make recommendations regarding what terms people with
disorders should use. Some patients (eg, those succeeding in part with
participation in social networks such as Alcoholics Anonymous) clearly find
benefit to calling themselves an alcoholic or an addict even if it might reflect
some internalized stigma. Other patients have strong negative associations to
being labeled a drug addict or alcoholic that do not aid in their treatment
engagement. Furthermore, patient acceptance of such labels has not been shown
to be necessary to achieve good clinical outcomes.
The purpose of this chapter is not to police language used or to call out those
who use a term with good intentions. It takes time for language to change in
society and even in clinical practice. Doing so now in clinical and scientific
speaking and writing is the beginning of that process and will ultimately lead to
wider use of accurate nonstigmatizing terms (29). Thus, this chapter has made
recommendations regarding terms that should be preferred versus those that
should be avoided. In general, stigmatizing terms should be avoided, as should
disease first constructions. Terms to be avoided by clinicians and scientists
because they may be potentially stigmatizing or clinically unclear are outlined in
Table 2-1; however, this table is not exhaustive. Scientific and medical terms that
are clearly defined and nonstigmatizing are preferred over vague inaccurate
terms, terms that are difficult to define, and terms that are used to mean many
different things. Better use of terminology can improve clear communication of
addiction science and improve quality of care for patients.
TABLE 2-1 Recommendations for Nonstigmatizing,

More Clinically Accurate Language
aCurrently marijuana (the plant leaf, stems, and seeds) is not typically sold as medicinal grade or
conclusively researched as having more benefits than risks, nor is it FDA approved. Moreover, cannabis is
the term more internationally used and is more descriptive relating to compounds being researched to
explore medical value—such as cannabidiol.
bCould be used if clearly defined and most useful for prescription drug (misuse) when the nature or
severity of the condition is unknown. Avoid calling the person a problem or their use a problem.
cCan be useful for public health messaging but needs to be clearly defined as it is sometimes used to mean
a heavy drinking episode but also used to mean several days of long episode of heavy drinking or other
drug use (eg, cocaine).
dThis term will likely continue to be used, but it should not imply a binary process (abstinent vs. relapse)
that does not reflect real typical clinical course (that can include lapses or in-between states).
eA similar term is not typically used for other drugs with addiction liability. This term seems to place
tobacco in a category different than other drugs, which may not be helpful considering its high addiction
risk and high morbidity and mortality. More favored terms for “smoking” include “tobacco” (or
“nicotine”). Further, “cessation” (or abstinence) while highly desired should not be the only goal. Smoking
reduction may have limited health benefits related to smoking and may also reduce relapse rates with other
substances used by the patient. However, the evidence for smoking reduction having health benefits related
to smoking is low, and these results are small compared to complete abstinence.
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CHAPTER 3
The Epidemiology of Substance Use
Disorders
Rosa M. Crum
CHAPTER OUTLINE
Introduction
Some EpidemiologicAL Principles
Alcohol Use Disorders
Drug Use Disorders
Recent Trends of Alcohol, Tobacco, and Illicit Drug Use
Remission from Substance Use Disorders
Correlates and Suspected Risk Factors
Comorbidity of Alcohol and Drug Use Disorders
Conclusions
INTRODUCTION
This chapter is organized to cover several areas. First, a few epidemiological
terms and types of epidemiological studies are discussed. Second, some of the
literature regarding prevalence, incidence, and trends of alcohol and drug use
disorders is reviewed. The remainder of the chapter is devoted to discussing
some of the correlates and risk factors associated with substance use disorders.
SOME EPIDEMIOLOGICAL PRINCIPLES

Epidemiology has been defined in several different ways but may be considered
the study of how diseases are distributed in populations as well as the study of
the determinants of disease and health (1–3). Some basic terms used in
epidemiology deserve attention in this chapter, because they are helpful in
understanding the literature and some of the studies reported here. Prevalence
generally is taken to represent the ratio of the total number of cases of a
particular disease divided by the total number of individuals in a particular
population at a specific time. Incidence refers to the occurrence of new cases of
a disease divided by the total number at risk for the disorder during a specified
period (4). Prevalence takes into account both the incidence and duration of a
disease, because it depends not only on the rate of newly developed cases over
time but also on the length of time the disease exists in the population. In turn,
the duration of the disorder is affected by the degree of recovery and death from
the disease. Incidence generally is taken to represent the risk of disease, whereas
prevalence is an indicator of the public health burden the disease imposes on the
community (4).
The strength of association between a particular characteristic and the
development of disease generally is represented by the relative risk. The relative
risk measures the incidence of disease among those with a particular
characteristic (such as family history of alcohol addiction), divided by the
incidence of disease among those without exposure to that characteristic. If there
is no difference in the incidence among those with and without the characteristic,
the ratio is equal to 1. The odds ratio is also a measure of the strength of
association between a characteristic and disease or other outcomes. A relative
risk or odds ratio >1 indicates a positive association of disease with a given
characteristic. A relative risk or odds ratio <1 signifies a negative association,
which may indicate a protective effect associated with the characteristic.
Excellent detailed discussions of epidemiological study designs can be found
elsewhere (1,2,4,5). For the purposes of this chapter, epidemiological studies can
be divided into two types: (a) observational and (b) experimental. Observational
studies may include cross-sectional, case–control, or cohort studies. In cross-
sectional studies or surveys, participant characteristics, risk factors, and disease
occurrence or other outcomes are evaluated (eg, by interview or physical
examination) at the same point in time (4). Analytic studies usually are classified
as case–control (retrospective) or cohort (longitudinal, prospective). Analytic
studies generally test a hypothesis of a suspected association between a
particular exposure (risk factor) and a disease or other outcomes. In all
observational studies, the investigator observes the study participants and gathers
information for analysis (4). In contrast, with experimental studies, such as
randomized clinical trials, study groups are selected, and often an intervention
(such as a new type of treatment) is given to one group of participants. The study
participants are followed, and the outcomes of each group are measured and
compared.
A number of major surveys in the United States and other nations have
assessed the prevalence of addiction. Comparison of these studies sometimes is
difficult because they employ different measures and definitions of addiction.
Some surveys have used structured interviews according to the criteria that have
become universally recognized, such as the Diagnostic and Statistical Manual of
Mental Disorders, most recently in its fifth edition (DSM-5) (6), and the
International Classification of Diseases, now in its 10th revision (7). Throughout
the text, when we use the term substance use disorder, we are referring to
substance abuse and/or dependence (diagnoses prior to DSM-5). In the DMS-5,
these separate diagnostic categories, among other changes, were removed and
combined. One of the earliest surveys to assess the epidemiology of substance
use disorders in the United States using a structured psychiatric interview was
the National Institute of Mental Health’s Epidemiologic Catchment Area (ECA)
study (8–10), conducted between 1980 and 1984 with a 1-year follow-up. At the
baseline interview, collaborators in the ECA assessed a probability sample of
more than 20 000 adult participants in five metropolitan areas of the United
States. Other major surveys that have provided information on substance use
disorders in the United States include the National Comorbidity Survey (NCS),
first administered between 1990 and 1992 (11), with a 10-year follow-up of a
subsample of the original survey, which included those who screened positive
for any disorder assessed in the first survey (12,13).
The National Epidemiologic Survey on Alcohol and Related Conditions
(NESARC), sponsored by the National Institute on Alcohol Abuse and
Alcoholism, was first conducted in 2001-2002, with a prospective follow-up in
2003-2005, and provided lifetime and 12-month estimates of substance use
disorders based on DSM-IV criteria (14,15) using the Alcohol Use Disorder and
Associated Disabilities Interview Schedule (16,17). The NESARC III,
completed in 2012-2013, did not involve longitudinal follow-up of wave 2 but
was an independent cross-sectional sampling of the US population, based on
DSM-5 criteria (18,19). To date, it is likely the largest nationally representative
survey in the United States that provides 12-month as well as lifetime prevalence
of DSM-5 substance use disorders. With the fifth edition of the DSM, in addition
to removing the separate abuse and dependence diagnoses, now combined into
one classification (eg, alcohol use disorder), other changes included having legal
problems as a result of substance use removed as a criterion. Furthermore,
experiencing craving for the substance was added to the criteria. The diagnosis is
met when at least two of the eleven criteria are met. In addition, the severity of
the substance use disorder is defined based on the total number of criteria met: 2-
3 (mild), 4-5 (moderate), and 6 or greater (severe) (6).
ALCOHOL USE DISORDERS

Prevalence
The overall prevalence of DSM-5 12-month alcohol use disorder is 13.9% with
12-month prevalence estimates of mild 7.3%, moderate 3.2%, and severe 3.4%
(19). Almost a third of the population meets the criteria for DSM-5 alcohol use
disorder at some point in their lifetime: overall lifetime prevalence is 29.1%,
with 8.6% having mild, 6.6% moderate, and 13.9% severe lifetime alcohol use
disorder. Consistent with earlier findings and other surveys, data from the
NESARC III show that alcohol use disorder is found to be higher among males
(17.6% and 36.0% 12-month and lifetime prevalence, respectively) than among
females (10.4% 12-month and 22.7% lifetime prevalence) (19). Most studies
have found that the prevalence of alcohol use disorder is highest among young
adults. For example, prevalence of 12-month alcohol use disorder was highest
among the 18- to 29-year-old age group in the NESARC III, and prevalence
decreased among older age groups (19).
The most recent prior year estimates of alcohol use disorder in a population-
based sample of the United States come from the annual National Survey on
Drug Use and Health (NSDUH). Since 2000, the NSDUH has gathered
information on prior year prevalence of substance use disorders based on DSM-
IV criteria. Data from the most recently available survey, the 2016 NSDUH,
indicate that 5.6% of survey participants met the criteria for DSM-IV alcohol use
disorder (abuse or dependence) in the prior year. The highest prevalence for past
year DSM-IV alcohol use disorder was found for young adults aged 18-25 years
(10.7%) (20,21).
Differences in estimates across surveys may be due to variations in the
diagnostic instrumentation, the version of the DSM that was used at the time the
survey was completed, the size of the survey sample, and the locale of the survey
participants (nationally representative samples vs. individual communities), as
well as specific characteristics of the populations surveyed, including the age
range of study participants. For example, the NCS included a relatively younger
population (persons ages 15-54 years) than some other surveys (22), and the
NSDUH includes individuals from age 12 years and older (20,21), whereas the
ECA and NESARC surveys gathered information for participants age 18 years of
age and above (8–10,15,19). In addition, specific methods used during data
gathering (eg, self-administered computerized vs. face-to-face interviews, use of
identifiers for follow-up assessment vs. anonymity) (23), or a focus on clinically
significance criteria (24) may relate to differences in survey findings.
Differences in survey findings also may occur from use of “gated” procedures
(25). For example, to maximize efficiency, in some prior surveys, only
individuals who screened positive for substance abuse were assessed for
substance dependence. This approach was evaluated in several analyses that
reported relatively small differences in estimated prevalence for ascertainment of
some types of DSM-IV substance dependence (ie, cannabis, cocaine) when
“gated” as compared with “ungated” protocols were in place (25,26), but
possibly more appreciable differences in assessment for other substances (ie,
alcohol) (27). As a consequence, some individuals with what was defined as
substance dependence may not have been identified among population-based
surveys when gated procedures were used (27,28). In some assessments, these
cases appeared to have been less likely to have received treatment and therefore
less likely to have been clinically apparent cases but more likely to have
occurred among specific subgroups of the population, such as among women
and racial–ethnic minorities (28,29).
Incidence
Compared with information from cross-sectional surveys, prospective data
gathered over time are less available; consequently, there is less information on
incidence rates for substance use disorders in the general population. Early data
from the Swedish Lundby study provide one of the few estimates of incidence of
alcohol use disorder over a prolonged follow-up period (30). The Lundby
community was interviewed for the first time in 1947, reinterviewed in 1957
(with 1% lost to follow-up), and then examined again in 1972 (30–32). The
investigators found that, among males, the overall age-adjusted annual incidence
of alcohol abuse or dependence (alcohol use disorder) was 0.3%. They further
found a general decline in incidence with age, with a sharp drop in incidence of
alcohol use disorders among men, beginning in their thirties (30). Of the 925
women examined in the Lundby community in 1972, only 3 were identified as
having an alcohol use disorder (31).
Fillmore examined longitudinal data from population-based US samples and
also found that incidence of unhealthy alcohol use and drinking problems
generally was lower for women than for men and that incidence for both men
and women declined with age (33,34). Fillmore’s findings also indicated
different patterns of drinking by gender. For example, women tended to develop
problems associated with drinking later in life than did men, and women were
found to have higher rates of remission across all age groups than did men (34).
Data from the 1-year follow-up of the ECA are consistent with other prospective
studies. Among men, the estimated annual incidence of alcohol use disorder in
the 1-year follow-up of the ECA was 3.7 per 100 person years, and for women,
the overall incidence was lower, 0.6 per 100 person years (35). The peak
incidence for both men and women was among those in late adolescence and
young adulthood, 18-29 years of age. Analyses using the extended follow-up
from the Baltimore site of the ECA (mean 12.6 years of follow-up, between
1981 and 1996) show similar trends for the development of alcohol dependence
(36). The most recent prospective data from the NESARC have provided annual
incidence rates for DSM-IV alcohol abuse and/or dependence (alcohol use
disorder) (1.66 per 100 person years) and also indicate that the greatest risk for
alcohol use disorder occurs during young adulthood (37).
DRUG USE DISORDERS
Prevalence
Several major surveys regularly estimate the prevalence of drug use in the
United States (eg, the NSDUH (20), the Monitoring the Future (MTF) National
Survey (38)). The NESARC III survey has provided data on the prevalence of
12-month and lifetime DSM-5 drug use disorders, the most recent edition of the
Diagnostic and Statistical Manual of Mental Disorders (6). In addition to the
changes in diagnostic criteria mentioned in the discussion for alcohol use
disorder, there was also the addition of cannabis withdrawal criteria. In the
NESARC III, prevalence of drug use disorder included the assessment of the
following substances: sedative (tranquilizer), cannabis, amphetamine, cocaine,
opioids (heroin and nonheroin), hallucinogen, club drugs (such as ecstasy,
ketamine, and 3,4-methylenedioxymethamphetamine), and solvent (inhalant)
(39). Tobacco is assessed separately from the group classification of drug use
disorder, which are primarily illicit substances. From the NESARC III survey,
overall 12-month prevalence of DSM-5 drug use disorder is 3.9%, with 1.9%
mild and 2.0% moderate to severe. Lifetime prevalence of DSM-5 drug use
disorder is 9.9%, with 3.4% mild and 6.6% moderate to severe (39). In the most
recent NSDUH from 2016, 12-month prevalence of drug use disorder based on
DSM-IV was reported as 2.7% among participants 12 years of age and older
(20). As discussed with regard to alcohol use disorder, men generally are found
to have a higher lifetime prevalence of drug use disorders overall, with higher
prevalence among young adults (20,39). As indicated previously, differences in
data collection methodology as well as diagnostic instrumentation may account
for some of the variations found in prevalence estimates reported from different
surveys (23).
From the 2016 NSDUH, we know that 28.5% of the population report use of
tobacco products within the prior year, most smoking tobacco cigarettes (20,21).
Data from the NESARC III indicate that 20.0% of the population met the DSM-5
criteria for nicotine/tobacco use disorder in the prior year and 27.9% have a
history of nicotine/tobacco use disorder during their lifetime (40).
Incidence
There is a relative paucity of information regarding the incidence of drug use
disorder as a group, with less information available for specific drugs. Early
findings from the 1-year prospective ECA data showed that the incidence of
illicit drug use disorders as a group was 1.09 per 100 person years of risk (35).
Analyses of the 3-year prospective NESARC data have provided more recent
estimates for the rate of development of drug use disorders: annual incidence of
drug use disorder was reported to be 0.31 per 100 person years. In both
prospective studies, men developed drug use disorder at a higher rate than
women, with the highest rates found for young adults. Incidence rates dropped
sharply after young adulthood, with extremely low or zero incidence among the
oldest participants (35,37).
RECENT TRENDS OF ALCOHOL,

TOBACCO, AND ILLICIT DRUG USE
New trends are continually being assessed by ongoing surveys and provide
important information regarding trends of use over time as well as surveillance
of newer substances. Assessment of trends in alcohol use and alcohol use
disorders comparing data from the cross-sectional NESARC surveys, completed
in 2001-2002 and in 2012-2013, is described in a recent report (41) and indicates
that 12-month alcohol use and alcohol use disorder increased over time. Alcohol
use rose from 65.4% reported in 2001-2002 to 72.7% in 2012-2013; similarly
alcohol use disorder increased from 8.5% to 12.7% of the population (41). The
largest increases were found for women, older adults, individuals in lower
socioeconomic groups, and race–ethnic minorities. These findings differ
somewhat with data from the most recent available NSDUH survey completed in
2016, which indicates that approximately half (50.7%) of the US population
report current drinking (having at least one drink in the past month) and 64.8%
report drinking in the prior year (20,21). Over the past one and a half decades,
the proportion of current drinkers remained essentially unchanged based on the
NSDUH. Estimates from the NSDUH surveys indicate that in 2002 among
individuals 12 years and older, 51.0% reported current drinking in the prior
month, 22.9% described binge drinking, and 6.7% were reported to be heavy
drinkers (42). Binge drinking, as defined in the NSDUH, is the consumption of
five or more drinks (males) or four or more drinks (females) at the same time or
during a short period of time (hours) for at least 1 day in the past month (20,21),
whereas heavy drinking is defined as binge drinking for at least 5 days in the
past month. The findings for binge and heavy drinking reported in the 2002
NSDUH are similar to reports from the 2016 NSDUH: 24.2% reported binge
alcohol use and 6.0% reported heavy drinking.
Use of tobacco products in general has shown some declines over the prior
one and a half decades based on data from the NSDUH (20,42) from an
estimated 30.4% prior month prevalence in the population in 2002 to the most
recent 23.5% in 2016. However, these estimates vary by age group, gender, and
race–ethnicity. Adolescence cigarette tobacco use in other data sources also has
shown declines over the past one to two decades including the MTF surveys,
sponsored by the National Institute on Drug Abuse (43); but these declines have
leveled off in the past couple of years. Furthermore, there are new trends: for
example, electronic or e-cigarette use is more common among US youth than
traditional cigarettes. In the MTF 2016, traditional tobacco cigarette use among
8th graders was 2.6%, yet e-cigarette use was reported to be 6% with
corresponding prevalence among 10th graders being 4.9% and 10%, respectively
(43). Unfortunately, there is also evidence that nonsmoking youth who begin
using e-cigarettes is more likely to subsequently transition to traditional tobacco
cigarettes (44,45).
Illicit drug use as identified by the NSDUH includes reported use of
marijuana or hashish, cocaine (as well as crack), heroin, hallucinogens, and
inhalants and/or nonmedical use of prescribed controlled substances (20). In the
2002 NSDUH, 8.3% of the population reported use of one or more of these
substances in the prior month. Data from the 2016 NSDUH indicated that 10.6%
reported past month illicit substance use. The most commonly used illicit
substance is marijuana, which had an estimated prior month prevalence of 6.2%
in 2002, decreased to a low prevalence of 5.8% in 2007, and in 2016 rose to
8.9%. Since 2011, information on synthetic marijuana has been gathered as part
of the MTF, which annually completes a school-based sample of 8th, 9th, and
12th graders in the United States. Prior year prevalence estimates for synthetic
marijuana among 12th graders peaked in 2011, when it was reported to be
11.4%. Since then, marked declines have followed with the most recent reports
of use among 12th graders in 2016 of 3.5% (43).
In the past two decades, there has been a massive increase in the use and
nonmedical use of opioids and of the rate and occurrence of deaths related to
their use (46). Trends indicate surges in prescriptions for opioids, which may
have fueled the misuse and subsequential epidemic of overdoses and opioid use
disorder (46). There is evidence to indicate that policies to limit prescription
practices appear to have helped to stabilize numbers of opioid prescriptions
(46–48). Yet, opioid prescription numbers remain large (49). Data from the 2016
NSDUH indicate that among individuals with nonmedical use of prescription
opioids in the prior year, 37.5% stated that their most recent source of
prescription opioids came from a physician, but 53% said that their most recent
source was from a friend or relative (either given by, bought from, or stolen
from) (20). Many individuals who use heroin report earlier nonmedical use of
prescription opioids (50–52). Furthermore, characteristics of individuals using
heroin have changed. Whereas in the past, heroin was considered a drug
primarily used by lower socioeconomically disadvantaged inner city individuals,
its use now has more broadly spread across a range of racial, socioeconomic, and
geographic subgroups (53,54). Recent evidence indicates that relatively large
increases in heroin use and opioid use disorder have been reported among White
young adult men and women and among those with prior nonmedical use of
prescription opioids (53,54). Comparison of data from the NESARC in 2001-
2002 to the most recent NESARC III completed in 2012-2013 indicates that
lifetime prevalence of heroin use increased from 0.33% to 1.6% (54). Recent
trends also indicate a surge of synthetic opioid use (55,56). A large proportion of
recent opioid deaths have been attributed to overdose due to synthetic opioids,
particularly fentanyl (56,57). Fentanyl and its associated analogs are all highly
potent, are relatively inexpensive to manufacture, and are often mixed with
heroin or other illicit drugs, or used as stand-alone substances (56,57). Because
of their high potency and rapid rate of action, most overdose deaths involving
these synthetic opioids have been causally linked to fentanyl or its derivatives
(56,57). A recent assessment of overdose deaths in ten US states, between July
and December 2016, completed by the Center for Disease Control and
Prevention indicated that 56.3% of the states’ reported opioid overdose deaths
involved fentanyl; furthermore, fentanyl was the stated cause of death in 97.1%
of the medical examiners’ and/or coroners’ reports (56). The illicit market for
production of these synthetic opioids is increasing, and the practice of mixing
these potent synthetic opioids with other drugs substantially increases overdose
risks (55–57). Greater surveillance of these illicit opioid sources and improved
availability of treatment options are needed (56,57). The public health impact of
opioid use remains a concerning challenge that will require a multifaceted
approach including prevention, intervention, educational as well as policy
initiatives (46,56).
REMISSION FROM SUBSTANCE USE

DISORDERS
Remission from substance use disorders such as alcohol use disorder in
community samples varies by individual characteristics (58,59) and subtype of
disorder based on age of onset, family history, specific disorder criteria, and
concurrent conditions including other substance use and psychiatric disorders
(60–63). For example, McCutcheon and colleagues found that abstinence from
alcohol use disorder was greater for those related to a first-degree family
member with alcohol use disorder abstinence compared to those with a relative
with persistent alcohol use disorder (61). Maintaining remission is also
dependent on consumption patterns while in remission. Using data from the
NESARC, Dawson et al. (64) assessed occurrence of relapse among individuals
who were in remission from DSM-IV alcohol dependence at the baseline survey
and found that at the time of the follow-up survey, ~3 years later, maintenance of
successful recovery from dependence was greatest for abstainers as compared
with other groups in remission that continued to drink.
Only a minority of individuals with substance use disorder report using
treatment services (including self-help groups, employee assistance programs,
inpatient and outpatient facilities, rehabilitation centers, crisis centers, healthcare
professionals, halfway houses, and withdrawal management units)
(15,19,39,65–67). Based on the data from the NESARC III, Grant et al. found
that only 13.5% of those with 12-month and 24.6% of individuals with lifetime
illicit drug use disorder reported receiving treatment (39). Among those with
alcohol use disorders, the proportion receiving treatment was even lower (7.7%
among those with 12-month alcohol use disorder and 19.8% of those with
lifetime alcohol use disorder) (19). A greater proportion of individuals with
moderate or severe substance use disorder enter treatment (19,39), and in some
reports, treatment is positively associated with having psychiatric disorder
comorbidity (65).
CORRELATES AND SUSPECTED RISK
FACTORS
Many correlates and suspected risk factors for alcohol and drug use disorders
have been examined. Some of these are discussed in this section for both alcohol
and drugs, because the suspected risk factors are similar and there are many
findings in common. This section is restricted to a discussion of a small selection
of personal or individual characteristics that have been found to be associated
with drug and alcohol addiction. The discussion is by no means exhaustive and
reviews only a fraction of the investigations in this area.
Gender
As discussed previously, alcohol use disorders and unhealthy alcohol use are
more common among males than among females. This consistent finding has
been shown in a number of cross-sectional surveys (11,15,19,20,22,31), as well
as in prospective studies (34,35,37,68). In the 2016 NSDUH (21), the occurrence
of past year alcohol use disorder was slightly less than twofold greater for males
(7.2% and 4.1% for males and females, respectively), and binge drinking in the
prior month among males (28.9%) was ~1.5 times higher as that for females
(19.8%); heavy drinking was twice as high for males than females (8.3% and
3.9%, respectively) (21). Differences in prevalence and incidence between men
and women have been attributed to a number of factors. Cultural norms, societal
standards, body size, hormonal environment, and differences in the metabolism
of alcohol all may contribute to the finding that women tend to use less alcohol
and to have lower occurrence of alcohol use disorder (69). However, studies in
the United States (70), as well as in other nations globally (71–73), over the past
couple of decades provide evidence that the gender gap for prevalence of alcohol
use disorder is narrowing, perhaps as the result of changes in drinking patterns
(70–75). Some hypothesize that changes in patterns of drinking among women
may be a result of deviations from traditional female social roles or related to
changes brought about by the increased number of women in the labor force, as
well as the combined input of home and work environments (76,77). Many
characteristics (eg, marital status, children in the home, full-time employment,
ethnicity, age, occupation, educational level), as well as the occurrence of life
events, and the presence of other psychopathology (such as depression) may play
a role in gender variability with respect to alcohol consumption and the
development of alcohol use disorder (78,79). In addition, there may be gender
differences in drinking as a response to stress with specific stressors (80,81).
Assessments across cultural groups have reported on the impact of gender equity
as well as social roles in explaining gender differences in drinking patterns
(82,83). In some subpopulations, there may be strong associations between
physical or sexual violence and alcohol use initiation (84) and the occurrence of
alcohol use disorder (85). A history of childhood abuse has been found to be a
potential predictor of women’s risk for alcohol and drug use disorders (86,87)
and may impact progression through stages of alcohol involvement (88).
There also are gender differences with respect to illicit drug disorders. Boys
and men generally have a higher prevalence (21,39) and incidence (37,89) of
drug use and use disorders than do females. In the 2016 NSDUH (21), the
overall proportion of illicit drug use in the past year among participants 12 years
of age or older was ~1.5 times larger for males (20.7%) than females (15.5%).
Similarly, the prevalence of past year illicit drug use disorder was ~1.5 times
higher for males (3.5%) than females (2.1%). The social or cultural restrictions
that are possible explanations for the reduced prevalence of alcohol use among
girls and women also may apply to some types of illicit drug use. Also, there is
some evidence for gender convergence for specific substances. For example,
recent evidence indicates that the gender gap for cannabis use prevalence has
narrowed (90). However, gender differences vary by the specific substance and
the age of use. For example, in the 2016 MTF, annual prevalence of any illicit
drug use as well as for particular substances including inhalants, tranquilizers,
and amphetamines was slightly higher among 8th grade girls than 8th grade boys
(38). Similar findings have been reported for any illicit drug use in the 2016
NSDUH. A prior year prevalence of 16.8% was found among boys aged 12-17
years, whereas for girls in the same age group, the prevalence was 18.1%. In
addition, some (91,92) but not all (93) studies have found that patterns of
progression may differ by gender. Using data from the NCS Replication, Wagner
and Anthony (91) found that males had a higher risk of progression from first
use to cannabis dependence, but there were relatively small sex differences in
progression risk for alcohol and cocaine. Yet, Keyes and colleagues using two
national surveys including the NESARC found that men progressed to alcohol
dependence at a greater rate than women (92).
Age
Prevalence of alcohol use disorder is generally lower among older adults
(15,19,94). This may occur for a number of reasons. Because the measure of
prevalence depends on the incidence as well as the duration of the disease
(1,2,4), alcohol use disorder may be less prevalent among the elderly because the
incidence decreases over the life span, the duration of the disorder is reduced, or
some combination of the two factors is in effect. If the duration of the disorder is
reduced, it may be a result of an increase in remission with age or a reduction in
survival. In other words, with age, prevalence may be reduced because fewer
individuals develop the disease, because the addiction problems have resolved,
or because addicted individuals die earlier. Explanations for a decreased
prevalence with age also may include a reduced tolerance to alcohol with age
(95), poorer recall among older adults, or a cohort effect (96). Further, the means
by which alcohol disorder is identified in young adults may not be relevant to the
elderly (97–101), with the result that unhealthy alcohol use may be
underrecognized in older adults (99,101,102). Surveys that include only
household participants may miss many with alcohol use disorder who reside in
nursing homes; also, older community residents with alcohol use disorder may
be less willing to participate in household surveys. Findings from prospective
studies show that incidence of alcohol use disorder generally declines with age
(36,37). The hazard rate for DSM-IV alcohol abuse and dependence was reported
to be highest at approximately age 19, and a steady reduction in hazard with
increasing age was found (15). However, problems related to alcohol use among
the elderly may occur at lower levels of consumption than in younger adults, and
older adults with alcohol use disorder may be at greater risk for comorbid
problems (103–105). Furthermore, at-risk drinking and subthreshold dependence
symptoms remain concerns and may be associated with negative outcomes
(106,107).
The age of onset of alcohol use has been investigated as a predictor of
subsequent problematic drinking and alcohol use (108–110). In general, the
earlier the age of first use, the greater the association with risk for subsequent
alcohol use disorder (110). In addition, early drinking onset is associated with
severity of pre–DSM-5 alcohol dependence symptoms (111), elevated risk of
alcohol-related injuries (112), motor vehicle accidents (113), physical violence
after drinking (114), the level of drinking in response to stressors (115), and
antisocial behaviors (109). Moreover, early-onset tobacco and other drug use
may be associated with an increased risk for the development of alcohol as well
as other drug use disorders (116,117). Earlier age of onset among women
observed in more recent birth cohorts has also been thought to be a possible
explanation for the rise in prevalence of alcohol use disorder among women
(118).
As was discussed for alcohol use disorder, age correlates with the occurrence
of drug use disorders. The highest prevalence and incidence rates for illicit drug
use disorders are found among individuals in late adolescence and young
adulthood (35,37,39). As with alcohol use disorder, incidence of drug use
disorder decreases with age (35,37). Onset of drug use disorders is the highest at
approximately age 19, with sharp declines thereafter, so that hazard rates after
age 25 are relatively low (65). In addition, early onset of drug use is associated
with elevated risk for subsequent substance use disorders (116,119–122).
Although incidence is low among older adults, and survival may be decreased
for individuals with drug disorders as they age, other factors also may be
involved. Prevalence may be lower among older adults because of a cohort
effect, because exposure and availability of illicit drugs differ by birth cohort.
For example, the current cohort of older adults had no access to crack cocaine in
their youth. When evaluating changes in the frequency of a disorder (in this case,
drug and alcohol addiction), distinctions need to be made between changes that
uniformly occur for all age groups during a particular historic period (period
effect), changes that occur with age as the individual matures (age effect), and a
cohort effect that reflects differences in disease rate for individuals born in
different years (123,124).
Some studies show that patterns of addiction have changed and show a
greater prevalence of alcohol and illicit drug use disorder among cohorts born
since World War II (70,125). Similarly, the risk of nicotine dependence has been
reported to be greatest among smokers in the more recent birth cohorts (126).
Evidence examining birth cohort associations with initiation of use for specific
substances also indicates that more recent birth cohorts have been more likely to
initiate drug use in childhood and early adolescence, particularly for cannabis,
cocaine, and nonmedical use of drugs (90), including nonmedical use of
analgesics (127,128). These patterns also have been reported in other global
areas (70,129–131). However, in some analyses, there is evidence of a broader
period effect across all age cohorts, which may explain the recent rise of
marijuana use in the United States (132).
Race and Ethnicity

Information on the relationship between alcohol and illicit drug use disorders
and racial and ethnic background is complex and sometimes conflicting. Some
of the inconsistent findings result from the relative paucity of data involving
ethnic and racial subgroups, the classifications used to group ethnic minorities,
variations in the social acceptability of drinking and drug use patterns within
cultural groups, and the relationship of socioeconomic status and the availability
of health care to racial and ethnic minority populations.
Findings from several studies indicate that drinking patterns among African
Americans differ from Whites (133,134). African American youth begin
drinking at older ages (93,135) and generally report lower levels of alcohol use,
intoxication, and episodes of heavy drinking (21). Prevalence estimates for
lifetime alcohol use disorder are also reduced relative to Whites (19,133,134).
Although the odds of alcohol use disorder tend to be lower for Blacks compared
with Whites, African Americans tend to suffer more medical and social
consequences from drinking, including injuries, higher mortality, and psychiatric
comorbidity (136–141). This may relate to differences in socioeconomic status,
access to health care, health service utilization, and drinking trajectories over the
life span as well as social and cultural environments (136,139,142–146). For
example, neighborhood poverty may have a greater effect on problems related to
unhealthy alcohol use among Black relative to White or Hispanic men (144).
When socioeconomic factors are taken into account, race differences are
sometimes attenuated (147–149).
In many reports, prevalence of alcohol use disorder is lower for Hispanics
relative to Whites (19,21). Yet, alcohol-related mortality is higher for Hispanic
relative to non-Hispanic White men, and deaths from liver cirrhosis differ by
race as well as ethnicity (138,150,151). Drinking trajectories, prevalence, and
incidence of alcohol-related problems and use disorders vary among Hispanic
subgroups in the United States (142,151–157), and variations may reflect factors
such as social and cultural environment, degree of acculturation, country of
national origin, generational status, and time since immigration (152,158–162).
In some studies, acculturation has been found to relate to binge drinking and
alcohol use disorder in addition to characteristics that may relate to drinking
such as suicide attempts and self-reported health status (159–163); and
associations may differ by gender (151). However, it is not clear if acculturation
influences alcohol use patterns for those seeking treatment or alters treatment
response (164,165).
Asian Americans generally have the lowest levels of alcohol consumption
and lowest prevalence of alcohol use disorder in the United States (19,21). There
is evidence that this in part may relate to their discomfort and sensitivity to
alcohol due to the physiological effects of the variants in alcohol-metabolizing
genes, such as aldehyde dehydrogenase genotypes (166–169), which are
relatively common in Asian subgroups. Genetic heterogeneity has been thought
to be one explanation for the lower occurrence of pre–DSM-5 alcohol
dependence among Asian populations (170), as well as among other racial
groups recently assessed (171,172). However, as with Hispanic Americans, the
Asian American population is composed of many subgroups with different
backgrounds and cultural drinking patterns (173,174), and nativity, immigration
status, acculturation, and ethnic identity have been found to be associated with
differential risk of alcohol use and use disorder outcomes (175–180).
Native Americans historically (19,21,181), and individuals from two or more
racial groups more recently (21), have the highest prevalence of alcohol use
disorder in the United States. Native Americans also have had the highest
drinking-related death rates (139,182,183). However, these findings are not
consistent across all studies (184), and it is not accurate to generalize findings to
all Native American populations, as drinking practices vary across tribal groups
(185–187) and cultural factors as well as socioeconomic characteristics and
psychiatric symptoms may play a role (181,188,189).
Prevalence of drug use and drug use disorders also varies by racial–ethnic
group (21,39,190). However, less information is available for drug use disorders
than for alcohol use disorders among different ethnic populations, particularly
for specific substances. In addition, persistence of drug use disorders varies by
race–ethnicity and gender and by number of substances used—with those with
polysubstance use being more likely to have persistent conditions (191,192).
Reports using data from the 2016 NSDUH indicate that the occurrence of past
year illicit drug use disorder among individuals 12 years of age and older was
highest among Native Americans, and among those indicating two or more
races, and lowest for Asian Americans (21). Similar relationships were
documented in analyses of 12-month prevalence using the NESARC III,
although there was no documentation for those from two or more racial
subgroups (39). However, there is limited evidence for differences in incidence
of drug use disorders by race–ethnicity as assessed with the prospective
NESARC data (37). In assessments of specific nonmedical prescription drug use
and disorders (sedative, tranquilizer, opioid, and stimulants), relative to Whites,
Black, Asian, and Hispanic subgroups were less likely and Native Americans
more likely to report use and to have lifetime substance use disorders (193,194).
As with alcohol use disorder, drug use disorder also varies by immigration
status, country of origin, acculturation, discrimination, and socioeconomic status
(195–202), and these influences relate to substance use in the United States
(195–198,200,201) as well as other nations globally (202,203). Patterns of
comorbidity, and drug-related correlates and consequences, such as arrest risk,
also vary by race–ethnicity (204–208). Furthermore, there are race–ethnic
differences in service utilization and criminal justice system involvement as well
as disparities in treatment of substance use disorders (209–214). Addressing
socioeconomic disparities and barriers to treatment, as well as cultural
competency in treatment settings, should help to improve treatment outcomes
across race–ethnicity groups (215–219).
Family History
Alcohol use disorder clusters in families (220,221) and family history of
pre–DSM-5 alcohol dependence may predict the severity of the disorder in
probands (222). Twin (223–226), adoption, and cross-fostering studies
(227–232) have attempted to answer the question of whether such familial
relationships are the result of genetic transmission or a shared environment.
Some characteristics such as early age of alcohol use appear to represent strong
genetic risk of alcohol use disorders (233). Genome-wide association studies
may provide evidence for specific genes that may be involved in alcohol use
disorder (234–236). There also have been genetic investigations of enzymes
involved in alcohol metabolism (170–172,237–239) and studies of genes
involved with neurotransmission as relates to alcohol dependence (240–242).
Although many studies have indicated a possible genetic relationship for alcohol
dependence, the association is complex. Evidence indicates that approximately
half of the risk may be attributed to genetic influences (226). However, many
individuals whose parents have alcohol dependence do not develop drinking
problems themselves, and many who develop alcohol use disorder do not have a
familial history of alcohol dependence. Clearly, environmental influences have a
major role (243,244).
Studies to assess the relationship of genetic liability with drug use disorders
have shown evidence for heritability involving nicotine (245–247), caffeine
(248,249), cannabis (250,251), and other illicit drugs such as cocaine, stimulants,
and opioids (252–258). Moreover, assessments of the liability for more than one
substance use disorder have provided some evidence indicating common genetic
vulnerabilities among diagnoses, such as pre–DSM-5 alcohol, nicotine, and
cannabis dependence (259–261), as well as with personality traits (262–264),
risk taking (265,266), and bulimic behavior (267).
Employment Status and Occupation

Employment, or working for pay, also is related to alcohol use and the
occurrence of alcohol use disorder (268–270). In the 2016 NSDUH, findings
indicate that most full-time employed individuals report having used alcohol in
the prior month (64.9%), which is higher than among the unemployed (49.7%).
However, there was no difference by the percent reporting binging in the prior
month (32.7% and 32.7% for the full-time employed and unemployed,
respectively) or by reports of heavy drinking (8.3% and 8.1%, respectively) (21).
Percent of full-time employees that had an alcohol use disorder in the prior year
was 7.0%, slightly lower than the percent among the unemployed (8.8%). Early
drinking behavior in youth may be associated with employment outcomes in
adulthood (271). However, working relatively long work hours may increase
alcohol and drug use among adolescents (272,273) and may influence drinking
during college (274). The prevalence of alcohol use disorder as well as alcohol-
related morbidity and mortality differs by type of occupation (268,270,275).
Higher prevalence of alcohol use disorder and higher mortality from disease or
injuries related to alcohol have been reported among those in occupations
associated with manual labor or those from lower socioeconomic strata
(270,275,276). However, some find that employment in high occupational strata
or in nonlabor jobs is associated with alcohol-related outcomes (275,277). In
addition, stressful working conditions including job insecurity and
dissatisfaction may be associated with drinking level (278–280). Poor
functioning due to drinking is associated with higher risk for unemployment
(281,282). Yet, job loss is associated with risk for morbidity and mortality
related to drinking (283). Furthermore, employment status may impact recovery
from pre–DSM-5 alcohol dependence (59).
In the 2016 NSDUH, a higher proportion of illicit drug use was reported
among individuals who were unemployed (20.8%) or employed part-time
(14.4%) than among full-time employees (11.1%). Prior year illicit drug use
disorder was also higher for the unemployed (8.0%) as compared with those
employed full- or part-time (2.4% and 3.7%, respectively) (21). Associations
with employment status may differ by specific substance type. Perlmutter et al.
found that unemployment was associated with nonmedical use of opioids,
whereas not being in the workforce was associated with nonmedical prescription
stimulant use (284). In a study of Canadian street-involved youth, Richardson
and colleagues found that being unemployed was associated with initiation of
injection drug (285). Relative to nondrug users, college students with persistent
drug use were more likely to be unemployed after college (286). Furthermore,
employment has been found to be associated with improved survival among
HIV-positive individuals who report illicit drug use (287). Findings from
analyses of the NCS indicate that high occupational strata are associated with
drug use disorders (277). Further, as with alcohol use disorder, there appear to be
differences in the prevalence of illicit drug disorders and tobacco cigarette
smoking associated with specific occupations (288,289). Yet, unless temporal
relationships can be well established (290), it is often difficult to know which
developed first, for example, whether lack of employment led to heavy drinking
or drug use or whether alcohol or drug problems resulted in job loss, inability to
obtain work, or selection into a specific occupation.
Marital Status
Marital status has been found to be related to the occurrence of alcohol use
disorders and drinking behavior, but as discussed regarding employment status,
understanding the temporal relationships may be difficult (291,292). Unhealthy
alcohol and drug use may predate the time that individuals make decisions about
marriage, and problems associated with drinking and drug use may be the reason
some individuals remain single or become separated or divorced. Analyses of the
NESARC indicate that individuals who never married or are separated, divorced,
or widowed are more likely than are married or cohabiting couples to have
prevalent or incident alcohol use disorder (19,37). Persons in stable marriages or
cohabiting had the lowest 12-month prevalence of alcohol use disorder (10.4%),
as opposed to adults who had never married (25.0%) or who were widowed,
divorced, or separated (11.4%) (19). However, depending on how marital status
is categorized, findings may differ. For example, in earlier analyses of the ECA,
cohabiting adults who never married had the highest prevalence of lifetime
pre–DSM-5 alcohol dependence (96). Marriage has been shown to relate to
decreases in subsequent risk for alcohol use disorder for both men and women,
and this potentially protective association was found to be strongest for those
with a positive family history of alcohol use disorder (291). Divorce and
widowhood appear to increase risk for alcohol use disorder; and subsequent
remarriage, among those previously divorced, is associated with reduction in risk
(293). Marital status may also interact with genetic risk (294,295). Furthermore,
there is evidence that recovery from alcohol dependence may be associated with
partners’ alcohol disorder status (296).
Prevalence of illicit drug use disorders also has been found to vary by
marital status. In analyses of the NESARC, individuals who never married
(classified separately from those who are cohabiting) have the highest
prevalence of drug use disorders (39). Lack of marital stability and the periods of
transition to and from marriage or divorce are associated with substance use,
treatment outcomes, and drug-related mortality (297–302). Alcohol and drug
use, particularly discrepant use between partners/spouses, impacts marital
satisfaction and functioning (303,304) and is associated with risk of partner
violence (305–307). Moreover, parental divorce, separation, or marital conflict
may increase risk for drug use initiation and use disorders in offspring (308,309).
However, utilizing couples therapy in addition to treatment of drug use disorder
may achieve improvements in marital functioning as well as substance use
outcomes (310).
Educational Level
Educational level often is included as part of broader socioeconomic or social
class characteristics (311), and studies of the relationship between educational
level and drinking patterns as well as the development of alcohol use disorder
may yield conflicting results. Some of the varying findings may be related to
how alcohol involvement is assessed. Recent analyses of the 2016 NSDUH show
that when examining current drinking status, the proportion who reported
drinking in the prior year increased with higher levels of education, whereas
reports of heavy alcohol use were lowest for those with less than a high school
education and for college graduates (21). Individuals without a college degree
have higher risk of alcohol use disorder relative to those with a college degree or
more (312). Higher school achievement and IQ during adolescence and young
adulthood are associated with reduced incidence of alcohol use disorder (313).
Moreover, dropping out of high school or leaving college early is associated with
an increased risk of alcohol use disorder in adulthood (314). These associations
are bidirectional in that early drinking and alcohol use disorders are associated
with the level of subsequent educational achievement (315). Genetic factors may
be associated with both alcohol-related problems and years of education (316).
Furthermore, the relationship of educational attainment with drinking level and
alcohol use disorder may differ by race–ethnicity (312,317).
Lifetime prevalence of drug use and drug use disorders also varies by
educational level. Data from the 2016 NSDUH indicate that past month illicit
drug use is lowest for adults who completed college (8.4%) compared to those
with less education (those with some college experience (13.2%) or who did or
did not graduate from high school [11.7% and 9.7%, respectively]). The
proportion of those with prior year illicit use disorder also is lowest for college
graduates (21). Eggert and Herting (318) found that high-risk youth (defined as
adolescents with a history of school problems and/or school dropout) had greater
access to drugs as well as greater adverse consequences from drug use relative to
students considered low risk (those defined as typical high school students).
Performance on some achievement tests is different and lower for substance-
using adolescents than for a comparison group of student controls (319), and
early education indicators may be associated with risk for subsequent drug use
disorders (320). Moreover, there is evidence of an association between marijuana
use and subsequent educational achievement later in life, indicating that those
with frequent and persistent use had lower subsequent educational attainment
(321,322). In addition, lower educational level is associated with nonmedical use
of prescription drugs (323). Parental educational level is also found to impact
substance use in offspring (324).
COMORBIDITY OF ALCOHOL AND

DRUG USE DISORDERS
Many clinical studies and assessments from household survey samples document
the comorbid occurrence of substance use disorders with psychopathology
(19,39,325–328). We focus in this section on comorbidity with psychiatric
conditions, but it is well known that substance use conditions are associated with
medical problems and risk for mortality (329–334). Regarding comorbidity with
psychiatric disorders, data from the NCS show that the majority of individuals
with a lifetime alcohol use disorder had at least one other substance use or
psychiatric disorder in their lifetime (11). In addition, some types of comorbidity
differ by sex (335–337) and may differ by race (136). Analyses of the NESARC
found positive associations for mood, anxiety, and personality disorders with
most substance use disorders (19,39). For example, Grant et al. (338) found that
all the independent mood and anxiety disorders assessed (those occurring
independent from symptoms of withdrawal and intoxication with the substances
involved) including major depression, dysthymia, mania, hypomania, social and
specific phobia, panic, and generalized anxiety disorders were associated with
DSM-IV alcohol and drug dependence. The temporal order of comorbid
psychiatric conditions with alcohol use disorders appears to occur
bidirectionally, although alcohol use disorder is more commonly the primary
condition (339,340). A large proportion of individuals with personality disorders
also have a comorbid substance use disorder (19,341), associations that may
have a genetic relationship (342). Personality disorders also appear to be
associated with persistence of drug use disorders (343). Furthermore, the
prevalence of alcohol use disorder with other substance use disorder comorbidity
is typically high. For example, the 12-month prevalence of alcohol use disorder
among those with a drug use disorder in the prior 12 months was more than 50%
for most substances assessed in the NESARC (344).
The prevalence of psychiatric disorders among individuals in alcohol and
drug treatment programs, or drug use among mental health patients in clinical
facilities, also shows high estimates but with wide ranges of prevalence
depending on the assessment methods, population characteristics, specific
diagnoses, and type of treatment setting (345–348). Outcomes tend to be worse
for individuals with co-occurring psychiatric and substance use disorders than
for those without the comorbid condition (eg, poorer psychological adjustment,
worse psychiatric symptoms, reduced treatment effectiveness, greater risk for
relapse, risky behaviors, homelessness, emergency room visits, rehospitalization,
and co-occurrence of medical problems) (349–359). Assessments of long-term
outcomes highlight the impact that co-occurring conditions can have on the level
of functioning, clinical status, and attainment in areas of educational level,
occupation, and social relationships (359–362). As more information becomes
available from longitudinal studies, it will be possible to better assess these
temporal relationships. In addition, future investigations into the progression of
symptoms will improve our understanding of possible etiological relationships
and should provide valuable information of potential clinical and treatment
applications.
CONCLUSIONS
This chapter has attempted to summarize a sampling of major findings in
epidemiological studies of alcohol and drug use and use disorders. As discussed
in detail by Kleinbaum et al. (124), epidemiological research aims to describe
the health status and distribution of disease in populations, as well as to identify
risk factors and potential etiological agents of disease, which may enable us to
better predict and prevent disease. The ultimate goals for the study of alcohol
and drug use epidemiology are to improve our understanding of causal
mechanisms, identify targets for prevention and intervention, and reduce the
prevalence of substance use disorder.
ACKNOWLEDGMENTS
Dr. Crum was supported by grants from the National Institute on Alcohol Abuse
and Alcoholism (AA00168, AA016346).
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CHAPTER 4
The Anatomy of Addiction
Thomas J.R. Beveridge, Colleen A. Hanlon and David
C.S. Roberts
CHAPTER OUTLINE
Introduction
Primer on Neuroanatomy
Neuroanatomy of Drug Reinforcement
Neuroanatomy of Drug Addiction
Moving Forward
INTRODUCTION
Dr. Watson admiring Sherlock Holmes “But consider! Count the cost!
Your brain may, as you say, be roused and excited, but it is a
pathological and morbid process, which involves increased tissue
change and may at least leave permanent weakness….Why should you,
for a mere passing pleasure, risk the loss of those great powers with
which you have been endowed?”—Sign of Four, Sherlock Holmes
(Arthur Conan Doyle, 1894).
This quote from Dr. Watson comes as a plea to Sherlock Holmes who has taken
up the bad habit of using cocaine in a “7% solution” when he is feeling bored.
This may be one of the first suggestions that regular use of psychostimulants
could change the structure of the brain—a fictional assertion from 221 Baker
Street, which can now be supported by shelves of brain imaging journals in the
nonfiction section of your local university. Over one hundred years later, we now
know that chronic use of many commonly used addictive drugs (including but
not limited to cocaine, alcohol, nicotine, and opioids) can lead to structural and
functional pathology in the brain. This pathology is not restricted to a single
brain region, a single cell type, or a single neurotransmitter system. Additionally,
the topography of drug-associated neural changes evolves in a spatially
progressive manner as the vulnerable individual progresses from a set of initially
rewarding experiences to addiction. This temporal continuum of substance use
disorder is now recognized by the DSM-5, and we are beginning to learn more
about its neural correlates.
There are three primary goals of this chapter. They include (a) introducing
the reader to a common set of neural regions, which appear to be critical to the
acquisition and maintenance of substance use disorders, (b) discussing changes
in these regions during the initial phases of reward-based learning, and (c)
concluding with a discussion of functional and structural neuropathology
associated with addiction. Whether we are observing young adults after a high
school football game, or rodents in cages in a research laboratory, initial drug
taking is nearly always a reinforced behavior. Consequently, in order to
understand why certain individuals may be more vulnerable to eventual
substance use disorders or addiction, it is critical to understand the neural
mechanisms that underlie basic drug reinforcement. Following a basic primer on
the neuroanatomy of addiction, Part 2 (Neuroanatomy of Drug Reinforcement)
focuses on the systems associated with the primary reinforcing effects of
psychostimulants, opioids, and cannabinoids. We focus on the site of action,
which defines the access points for a drug to influence a specific brain process
and highlights the role of the limbic system. In Part 3 (Neuroanatomy of Drug
Addiction), we will describe how an initial reinforcing drug action influences
brain areas beyond the limbic system, which are involved in habit formation and
maintenance of the initially reinforced behavior.
For the most part, the discussion of the anatomy of reinforcement and
addiction maps onto structures associated with the limbic system and the basal
ganglia.
PRIMER ON NEUROANATOMY
Multiple brain structures are involved in the addiction process. The structures
most often mentioned in the context of unhealthy substance use and addiction
are closely associated with the limbic system, lateral hypothalamus, basal
ganglia, and frontal cortical regions. Here we present a brief description of each
of these systems. Readers interested in a more complete description of the
anatomy of these regions are referred to the following reviews (1–3).
Limbic System
Research into the limbic system has a long and venerable history, but some
scholars have suggested that the term may have outlived its usefulness.
Nonetheless, a brief historic review of the term is a useful way of introducing
some of the regions involved in drug addiction. The term limbic is derived from
the Latin term limbus, meaning border, and was used to describe a ring of
phylogenetically older cortex that separates the diencephalon and the neocortex.
This limbic lobe consisted of the subcallosal area, cingulate, and
parahippocampal gyri (Fig. 4-1). This purely anatomic distinction was expanded
by MacLean (4) in 1952 to describe a functional unit that was proposed to be
responsible for emotional expression. He made the distinction between the older,
medial cortex and the more lateral neocortex, which is involved in cognitive
functions.
Figure 4-1 Regions of the human brain associated with the

limbic system, which includes a loop of cortex extending
from the subcallosal region through cingulate cortex to the
parahippocampal gyrus. Also shown are the hippocampal
formation, septum, amygdala, and mammillary bodies.
MacLean’s concept was that most human behavior is the result of cooperation
between three systems of the brain. The cerebral cortex is responsible for higher-
order reasoning and speech, whereas the limbic system was the source of
emotions, aspects of personal identity, and fight-or-flight instincts. The third of
MacLean’s system is the reptilian brain. Early work with primates showed that
when various parts of the limbic system were electrically stimulated, a range of
emotional responses was produced, such as rage, fear, and joy (5). This
phylogenetically older brain is responsible for the organism avoiding things that
are “disagreeable” and approaching those that are “agreeable”—reactions that
MacLean saw as having survival value. It is now clear that structures associated
with the limbic system (such as the hypothalamus, hippocampus, and amygdala)
are essential not only for learning and memory but also for the emotional context
and the affective response to learned associations.
As is detailed, many addictive drugs have their sites of action within the
limbic system, and the neurochemistry within these structures is altered during
the addiction process. This may help explain why decisions surrounding drug
seeking and drug taking seem to be driven more by emotion and instinct rather
than by logical.
From an anatomic perspective, MacLean defined the limbic system as the
original limbic lobe along with other structures sharing direct connections with
them. These include the olfactory cortex, hippocampal formation, amygdala,
septum, hypothalamus, habenula, anterior thalamic nuclei, and parts of the basal
ganglia. With further anatomic research, more and more areas were shown to
share direct connections with these structures and some of these began to be
included in the limbic system. The result was that the boundaries of the limbic
system became overly broad. Brodal (6) observed that the term limbic system
was becoming less useful, and he argued that it should be discarded altogether;
however, the concept of a phylogenetically older forebrain system responsible
for emotional control is now firmly entrenched.
Swanson (7) has helped crystallize the anatomic definition by characterizing
the limbic system as a network of highly interconnected regions that appear to
form the only major route for information transfer between the neocortex and the
hypothalamus. Figure 4-1 illustrates these areas in the human brain.
Interface of the Limbic System and the Basal

Ganglia
The basal ganglia is traditionally thought of as a motor system; however, the idea
that this system deals only with motor function while the limbic system deals
with reinforcement and emotion is oversimplified and entirely misleading. As
later sections illustrate, there is reason to believe that parts of the basal ganglia
are very much involved in memory formation and a variety of cognitive tasks.
As more is learned about how the basal ganglia and limbic system communicate,
it is becoming increasingly clear that the two systems are jointly involved in
coordinating motivated behavior.
The largest mass associated with the basal ganglia is the striatum (caudate–
putamen). The dorsal portion has long been considered part of the basal ganglia,
whereas the ventral striatum is considered to be part of the limbic system (8).
This dorsal/ventral distinction is clearly important; however, more recent debate
has focused on the idea that gradations rather than sharp boundaries mark the
transition from the dorsolateral to ventromedial striatum. Figure 4-2 shows the
topographic organization of inputs to the striatum in the rat. Voorn et al. (9)
make the point, as Figure 4-2 illustrates, that no histological or
immunohistochemical border exists that can be used to define or divide the
region. Note that although the dorsolateral parts receive primarily motor inputs
and the ventromedial striatal areas receive primarily limbic projections, it is a
gradual topographic transition.
Figure 4-2 Connections of the dorsal and ventral striatum.
Cortical and thalamic inputs to the striatum distribute in a
dorsomedial- to-ventrolateral manner. To paraphrase Voorn et
al. (9), afferents arising from the frontal cortex and projecting
to the striatum are depicted. Sensorimotor projections
innervate the dorsolateral striatum in a somatotopic fashion.
Vicerolimbic inputs project to the ventromedial striatum.
Areas in between dorsolateral and ventromedial striatum
receive inputs from higher cortical association areas: ac,
anterior commissure; ACd, dorsal anterior cingulate cortex;
AId, dorsal agranular insular cortex; AIv, ventral agranular
insular cortex; IL, infralimbic cortex; PFC, prefrontal cortex;
PLd, dorsal prelimbic cortex; PLv, ventral prelimbic cortex;
SMC, sensorimotor cortex. (Adapted from Voorn P,
Vanderschuren LJ, Groenewegen HJ, et al. Putting a spin on
the dorsal-ventral divide of the striatum. Trends Neurosci.
2004;27:468-474.)
The accumbens forms the ventral portion of the striatum, thus accumbens and
ventral striatum are used synonymously in the addiction literature. Famously, in
1993, Mogenson et al. (10) described the ventral striatum as the crossroad of the
limbic and motor systems and “the place where motivation is translated into
action.” Figure 4-2 also shows two regions identified as the nucleus accumbens
(NAcc) core and shell. The involvement of these two regions in the behavioral
and electrophysiological responses to drug reinforcement has been extensively
studied, and some debate has focused on which area is responsible for particular
drug effects. Some of the core–shell debate might eventually give way to
discussion of the function of subregions defined by projections.
In the primate, as one may expect, the organization of these striatal
connections is complex. Haber et al. (11) have described the topography of
striatonigrostriatal circuitry, that is, reciprocal synaptic connections between the
striatum and substantia nigra pars compacta/reticulata, and proposed how this
pattern of connections may provide a means through which information flow
between striatal regions can be achieved (Fig. 4-3). This circuitry can be
conceptualized as a series of ascending spiraling connections between adjacent
striatal regions via the ventral midbrain (substantia nigra), so that the accumbens
shell influences the accumbens core, the core influences the central striatum, and
the central striatum influences the dorsolateral striatum in turn.
Figure 4-3 Striatonigrostriatal connections form a series of

ascending spiraling loops. Projections from the NAcc shell
terminate in both the VTA and ventromedial SNc. The VTA
sends reciprocal projections back to the shell and neurons
from the medial SN project forward to the NAcc core. The
projections continue to go back and forth between the
striatum and substantia nigra, spiraling upward, so that the
shell influences the core, the core influences the central
striatum, and so on. These striatonigrostriatal connections
continue to occur even past the anterior commissure (top
right schematic). These posterior portions of the caudate and
putamen have reciprocal connections with the dorsal portions
of the SN. VTA, ventral tegmental area; SNc, substantia nigra
pars compacta; SNr, substantia nigra pars reticulate. (Adapted
from Haber SN, Fudge JL, McFarland NR.
Striatonigrostriatal pathways in primates form an ascending
spiral from the shell to the dorsolateral striatum. J Neurosci.
2000;20:2369-2382.)
Executive Function and Cortical Involvement

Executive function involves control over many aspects of behavior. Some of
these include the ability to differentiate among conflicting thoughts determine
good and bad, better and best, same and different, future consequences of current
activities, working toward a defined goal, expectation based on actions,
behavioral inhibition, and social “control.” The prefrontal cortex (PFC) is
thought to be the “hub” of executive function in the brain.
The PFC in humans is subdivided into three main regions: (a) the
orbitofrontal and the ventromedial areas, which are thought to be involved in
processing reward (12); (b) the dorsolateral PFC, more broadly involved in
decision-making (13); and (c) the anterior and ventral cingulate cortex, which
helps to control whether or not a particular behavior will be performed and to
what intensity (14).
NEUROANATOMY OF DRUG
REINFORCEMENT
“Site of action” is a pharmacological concept that defines the access point for a
drug to produce a specific response. If that response is defined behaviorally (eg,
anorexic, convulsant, antidepressant effect), then the site of action identifies the
receptors and brain regions responsible for that particular behavioral response. It
is one thing to describe all possible sites where a drug can affect the brain; it is a
more difficult matter to narrow down the possibilities to a particular binding site
in a circumscribed region. Research into the site of action for the reinforcing
effects of psychostimulant drugs, such as cocaine and amphetamine, offers a
good example of how this investigative process occurs.
In vitro experiments have shown that cocaine binds to dopamine,
noradrenaline, and serotonin (DA, NA, and 5-HT) transporters and blocks the
reuptake of these neurotransmitters (15); amphetamine acts additionally as a
releasing agent. Both of these actions result in an increased concentration of
monoamine neurotransmitters in the synapse. Therefore, psychostimulant drugs
act as indirect agonists everywhere these transmitters are found.
An examination of the anatomic projections of the catecholamine systems
shows that they have extensive and diffuse projections throughout the neural
axis. The cell bodies of these transmitter systems are loosely organized in an
anteroposterior fashion. Based on their histochemical mapping studies,
Dahlstrom and Fuxe (16) proposed a nomenclature wherein cell clusters were
numbered from posterior to anterior and given a letter prefix according to
whether they were dopaminergic/noradrenergic (A) or serotoninergic (B). Figure
4-4A shows the distribution of NA fibers. The locus coeruleus (LC) (A6) is
located in the dorsal brain stem and sends ascending projections to terminal
regions of the cortex, hippocampus, and cerebellum. More caudal and ventral
NA cells groups (A1 to A5) innervate the hypothalamus and brain stem.
Dopaminergic innervations are more circumscribed (Fig. 4-4B). DA cell groups
within the ventral tegmental area (VTA) and substantia nigra (A8, A9, and A10)
project in a topographic manner to the striatum. The more medial group (A10)
sends projections to the ventral striatum, whereas the more lateral groups form a
nigrostriatal bundle that innervates the caudate–putamen. This latter projection is
known to degenerate in Parkinson disease and is thus associated with motor
function. An additional cluster of DA cells in the hypothalamus composes the
tuberoinfundibular DA system, which innervates the external layer of the median
eminence. Dahlstroem and Fuxe (17) also described 5-HT cell groups (B1 to
B9), which lie near the midline of the pons and upper brain stem. Later studies
showed clusters of cells also in the caudal LC, area postrema, and
interpeduncular nucleus (14). Generally, the more caudal cell groups innervate
the medulla and spinal cord, whereas the more anterior clusters project rostrally
(Fig. 4-4C).
Figure 4-4 Schematic diagram illustrating the distribution of
the main central neuronal pathways containing noradrenaline
(A), dopamine (B), and serotonin (C). The location of cell
bodies of origin is indicated by circles with the projections
indicated by arrows.
The main point to be taken from an examination of the areas innervated by DA,
NA, and 5-HT is that there is hardly a region that is not innervated by at least
two of the monoamines. Given that psychostimulants have an effect at the
terminal regions of each of these systems, every area of the brain would be
expected to be affected to some extent by an injection of cocaine or
amphetamine. It has been a considerable challenge, therefore, sorting out what
transmitter in which particular area produces toxic effects and adverse reactions
on the one hand and pleasurable or positive reinforcing effects on the other.
Preclinical Studies of Drug Reinforcement

Experiments with nonhuman primates and a variety of other laboratory animals
have helped identify the important sites of action for drug reinforcement. It is
important to note that, early on, there was considerable skepticism whether
anything useful could be learned from laboratory animals regarding human drug
taking. Given the premise that only humans engage in unhealthy drug use, along
with the observation that what distinguishes the human brain from other
mammals is the development of the neocortex, the logical conclusion was that
this region is responsible for drug addiction. This idea fit well with the idea that
drugs were “mind expanding” and that the reasons why a person might take
drugs has to do with their effects on consciousness. Interviews with individuals
who use drugs and introspective analysis of drug-taking behavior suggested that
some of the reasons that people take drugs is for “pleasure, curiosity, the desire
to experiment, the sense of adventure, the search for self-knowledge, the relief of
stress and tension, depression, the feeling of powerlessness, and the lack of
belief in the future” (18). Although these observations are entirely appropriate
for discussion at one level, they also serve to perpetuate the idea that human
consciousness and reasoning are the bases for drug reinforcement. The
demonstration that nonhuman primates and rodents will voluntarily self-
administer drugs such as cocaine and heroin has prompted a consideration of
concepts other than human consciousness to account for use of drugs, forcing an
examination of brain regions other than the cortex.
There is an extremely high correlation between the addictive drugs that are
used by humans and drugs that are self-administered by other mammalian
species such as rat, dog, cat, rabbit, and nonhuman primate (19,20). These data
support the idea that addictive drugs have their reinforcing actions on brain
structures that have been relatively conserved through the course of human
evolution—that is, limbic and brainstem areas. This being the case, the
development of self-administration techniques, through intravenous (IV)
(21–23), intracranial (24–26), and inhalation (27) routes, has provided a means
to study brain structures responsible for drug reinforcement in animal models.
Psychostimulants
Pharmacological experiments were the first to narrow down the range of
possible sites of action for the reinforcing effects of psychostimulant drugs
(28,29). In these studies, rats and monkeys were trained to self-administer
cocaine and amphetamine until they showed a stable baseline level of
responding (Fig. 4-5). They were then pretreated with a variety of agonists or
antagonists in an effort to identify the specific transmitter systems that modulate
reinforcing efficacy. Importantly, it was shown that pretreatment with DA
receptor antagonists caused the animals to self-administer cocaine and
amphetamine more frequently (30–32). This is the same result one sees if the
concentration of drug is diluted: the animals appear to compensate for the
reduction in drug effect by increasing their intake. Note that pretreatment with
NA or 5-HT antagonists did not have consistent effects on drug intake. These
data prompted Wise (33,34) to champion the idea that stimulation of DA
receptors must be essential for psychostimulant reinforcement.
Figure 4-5 In self-administration studies, animals are
implanted with permanent indwelling catheters and placed in
an experimental chamber. The catheter is connected to a
syringe pump through a fluid swivel that allows free
movement throughout the chamber. A computer detects
responses on a lever and controls the timing of drug delivery
according to the schedule of reinforcement. For example, on
a fixed-ratio one schedule (FR1), every response on the lever
results in an infusion of drug.
Peripheral injections of DA antagonists narrowed the site of action to DA

receptors, but it remained unclear which brain regions mediated this effect.
Central manipulations were necessary to identify which brain regions were
important. Neurotoxins specific to catecholamine and indolamine neurons
provided a useful tool to examine whether the loss of a particular fiber system
would affect drug self-administration. A considerable literature developed
around the neurotoxin 6-hydroxydopamine (6-OH-DA) that, depending on the
site of injection and other parameters, could be used to completely deplete
various brain regions of either DA or NA. Early experiments showed that
removing the noradrenergic innervation of the entire forebrain had almost no
effect on cocaine self-administration. By contrast, removal of the DA innervation
of the NAcc resulted in a substantial reduction in cocaine’s reinforcing effects
(35–37). In fact, animals will no longer self-administer cocaine if DA levels in
the NAcc are reduced by more than 80%. Destroying the DA neurons in the VTA
also drastically reduced cocaine self-administration (38). These data were the
first to draw attention to the NAcc (more recently referred to as ventral striatum)
as a site for action for psychostimulant reinforcement.
6-OH-DA lesions in other brain regions have had much less dramatic effects.
Lesions of the dorsal striatum do not change the rate of cocaine intake,
supporting the idea that the ventral striatum has a preferential involvement (39).
Additionally, destruction of DA terminals in the medial PFC or amygdala has
only minor effects on the cocaine dose–response curve, which seems to reflect
changes in the reinforcing threshold or a change in the anxiogenic effects of
cocaine (40,41).
Injections of DA antagonists directly into the brain have also been used to
identify the important anatomic sites involved in cocaine action. The evidence
consistently shows that the DA receptors in the ventral striatum are an important
site of action. Blockade of D2 receptors produce an apparent decrease in
potency. That is, animals compensate by increasing their hourly drug intake and
will “work” less hard for each injection. Injections of D2 antagonists into the
dorsal striatum and the medial PFC produce similar effects, albeit less strongly
(42,43).
In summary, the data presented are from a wide range of studies using
neurotoxins, and specific pharmacological agents are consistent with the idea
that the most important site of action for the reinforcing effects of cocaine and
amphetamine is at DA terminals in the ventral striatum. It should be emphasized
however that, although the ventral striatum is essential for the reinforcing effects
of cocaine and amphetamine, other DA projection areas (such as the PFC,
amygdala, and dorsal striatum) also contribute to some extent.
The site of action for the locomotor-activating effects of psychostimulant
drugs seems to largely overlap with the regions responsible for drug
reinforcement. Experiments using either lesion or intracerebral injections of DA
drugs have shown that stimulation of the DA receptors in the ventral striatum
produces behavioral activating effects (locomotion); stimulation of DA receptors
in the dorsal striatum produces stereotypy (44), which is characterized by
repetitive sequences of movements, such as licking and grooming in rodents. 6-
OH-DA–induced destruction of DA terminals in the ventral striatum almost
completely abolishes the locomotor stimulant effects of cocaine, while lesions of
the dorsal striatum abolish psychostimulant stereotypy. Similarly, direct
injections of DA agonists into the ventral striatum produce locomotion, whereas
injections into the dorsal striatum produce stereotypy (45–47).
The stereotypic response elicited from the dorsal striatum may have
relevance to addiction. In rats, stereotyped behavior is often measured on a
categorical scale, which includes licking, chewing, and gnawing. These high-
frequency movements have the appearance of being “hard-wired” responses that
are elicited by the drug. It should be emphasized, however, that almost any
behavior can become stereotyped. In their influential article, Randrup and
Munkvad (48) described how the precise forms of stereotyped behavior differ
across species and offer the example of a man who repeatedly rebuilt his car
engine. They suggested that inhibition of drug-induced stereotypy might be
useful in screening antipsychotics. We know now that this is true because of the
relationship between the importance of DA in stimulating stereotypy and the
action of neuroleptic drugs. To re-emphasize, anything can become stereotyped.
Behaviors that occur with high frequency have a high likelihood of
becoming stereotyped (ie, they occur repetitively and ritualistically) if they occur
in the presence of a drug (49). Lyon and Robbins (50) argue that stereotypy is a
process in which there is an increase in frequency, in a diminishing number of
response categories. The effect is that psychostimulant drugs narrow the
behavioral repertoire such that only a few predominant behaviors remain. Put
another way, the behavioral repertoire becomes focused around the things that
occur most frequently. In the case of a person with addiction, the frequent
behaviors associated with drug seeking and drug taking become repetitive and
ritualistic.
In conclusion, strong evidence from studies using widely different strategies
suggests that stimulation of DA receptors in the ventral striatum is associated
with drug reinforcement. There is a wealth of evidence from a parallel literature
showing that the mesolimbic DA system is also involved in reward from natural
behaviors such as feeding (51–53), drinking (54,55), sexual behaviors (56,57),
and intracranial self-stimulation (58–60). This enormous amount of literature has
resulted in the mesolimbic DA system being called a reward pathway. Whether
this term is accurate or biologically meaningful (we think it is not) lies outside
the scope of this chapter. However, the immense interest in the mesolimbic DA
pathway demands some discussions of its interconnections.
Data from electrophysiological studies show that VTA-DA neurons respond
to primary reinforcing stimuli (eg, food) and to environmental cues that predict
the presentation of rewards (61,62). It is therefore surprising that these neurons
receive no direct input from visual, auditory, or somatosensory systems (63). It
appears instead that the VTA is a part of, and receives inputs from, a widespread
collection of neurons that belong to the “isodendritic core” (64). This system is a
network of neurons stretching from brainstem to telencephalon. The neurons
within the network have similar morphology, send out long projects, and are
themselves the target of a great number of contacts from distant sources (65). It
would appear that this network serves an integrative function and responses to
changes in the environment that are biologically significant. At present, it
remains unclear whether the VTA-DA neurons respond differentially than others
in the network and whether they are specifically activated by reward or more
generally by any other important stimulus.
Opioids
Again, the process of identifying the site of action for the reinforcing effects of
opioid begins with identifying all possible receptors sites. Opioid receptors are
expressed throughout the brain, especially in limbic and limbic-related
structures; they are found in the amygdala, insular cortex, caudate, anterior
hypothalamus, cortex, parietal cortex, putamen, thalamus, and periaqueductal
gray (66). There are three different types of G protein–coupled opioid receptors:
μ, κ, and δ, which are acted on by both endogenous and exogenously applied
opioids (67). Selective μ agonist drugs, such as morphine, heroin, and most
clinically used opioid analgesics, produce analgesia, euphoria, respiratory
depression, emesis, and antidiuretic effects. Selective κ agonist drugs, such as
the experimental compounds ethylketazocine and bremazocine, produce
analgesia, dysphoria, and diuretic effects, but no respiratory depression. There is
less known about the direct role of δ receptors. Agonists at μ receptor are more
likely to have misuse and addiction liability than κ agonists (68–70). Within the
dorsal and ventral striatum, there are areas of overlap between expression of
opioid receptors; however, their expression patterns tend to differ. μ Receptors
are expressed in patches, and κ and δ receptors are more diffusely distributed
(71).
Almost all that is known about the neurobiology of opioid reinforcement is
derived from animal models. Three approaches have been used to investigate the
involvement of various brain regions in opioid reward: (a) intracerebral self-
administration of opioid agonists, (b) blockade of IV heroin self-administration
by intracerebral injections of opioid antagonists, and (c) disruption of IV heroin
self-administration by lesions. Generally, the focus has been on areas associated
with the mesolimbic DA system (ventral striatum and VTA), although other
regions have also been implicated.
Self-administration of drugs directly into various brain regions would seem
to be the most straightforward test of their involvement in reinforcement
processes; however, the procedures have a number of technical problems that
limit their appeal. Issues involving diffusion, osmolarity, and tissue damage
demand thoughtful controls (see Ref. 72 for review). Nonetheless, several papers
have provided evidence that opioid-like compounds are self-administered into
discrete brain regions. The early work focused on the lateral hypothalamus
(24,73,74) because this area was intensely studied for its ability to support
intracranial electrical self-stimulation (75). Later, because of interest in the
mesolimbic system, interest switched to the ventral striatum and the VTA. The
role of the lateral hypothalamus has been challenged, and it is possible that the
early results were due to diffusion of drug to other areas (76). The ventral
striatum appears to support intracranial self-administration of morphine (77) and
methionine-enkephalin (78). These data fit well with the demonstration that
intra-NAcc opioids produce a conditioned place preference (79). Techniques
have also been developed to study intracerebral self-injection in mice by using a
Y-maze. Selection of one arm of the maze results in a morphine injection,
whereas the other arm results in a saline injection. Using this method, mice have
been shown to self-inject morphine into the lateral septum (80) and the ventral
striatum but not the dorsal striatum (81).
By far the most sensitive site for intracerebral self-administration of opioids
is the VTA. Both μ and δ opioids are self-administered into this region at doses
that are not supported in other areas (26,82–84). The idea that opioids have a
significant impact on reinforcement mechanisms through an action in the VTA is
supported by a variety of other techniques. For example, injections of opioid
agonists into the VTA also produce a conditioned place preference (85), facilitate
brain stimulation reward (86,87), and reinstate extinguished lever responding
that was trained under IV heroin reward (88).
It should be noted that there are a few reports of reinforcing effects produced
by intracerebral injections of opioids into the hippocampus (89) and
periaqueductal gray. The doses used in these studies are relatively high, and it
remains unclear whether these are important but less sensitive sites or whether
diffusion of the drug to other areas accounts for the data.
When self-administering IV heroin, animals respond to a decrease in the unit
injection dose by taking injections more frequently. A similar phenomenon can
be observed when animals are treated with a systemic injection of naloxone (a μ
antagonist), suggesting that animals compensate for a reduced drug effect by
increasing their intake (90). Several laboratories have used this compensatory
response to evaluate the effects of opioid antagonists injected into various brain
regions. Increases in IV heroin self-administration have been shown after
injections of low doses of opioid antagonists into the NAcc (91–93),
periaqueductal gray (92), stria terminalis (94), and lateral hypothalamus, but not
the PFC (95). Surprisingly, injections of an opioid antagonist into the VTA have
relatively little effect (96). It remains unclear why many studies have shown that
the VTA is one of the most sensitive brain sites for intracerebral self-
administration of opioid agonists, whereas it is one of the least effective sites for
disrupting IV heroin self-administration studies with an intracerebral injection of
opioid antagonists.
Lesions offer a third method for identifying critical brain areas responsible
for the reinforcing effects of opioids. Zito et al. (97) showed that the size of a
kainic acid–induced lesion of the NAcc correlated with impaired heroin self-
administration. This effect is site specific because lesions of other areas, such as
the lateral hypothalamus, do not necessarily affect heroin self-administration
(98). More recent studies have attempted to define the relative contribution of
subregions within the ventral striatum comparing acquisition of heroin self-
administration after excitotoxic lesions of the NAcc core or shell. Rats with
lesions of the NAcc core lesion group showed impairments in acquisition,
whereas the group with lesions of the NAcc shell was similar to controls. This
effect was found either with acquisition of low-dose heroin on a simple fixed-
ratio schedule (99) or with acquisition of a second-order schedule with a high
injection dose (100). These data suggest a relatively greater role for the NAcc
core in the acquisition of heroin-seeking behavior.
Martin et al. (101) examined regional differences in the ventral striatum by
using beta-FNA. This drug is an irreversible antagonist at the μ-opioid receptor
producing what amounts to a reversible lesion. Beta-FNA blocks the receptor
rendering it unavailable for many days, until new receptor populations can be
synthesized. Beta-FNA was found to produce site-specific effects, attenuating
heroin self-administration when injected into the caudal but not rostral NAcc.
The hypothesis that the mesolimbic DA systems mediate the reinforcing
effects of opioids has been proposed. Certainly, it is clear that psychostimulants
and opioids have independent sites of action at the receptor level. DA
antagonists potently affect cocaine but not heroin self-administration;
conversely, opioid antagonists potently affect heroin but not cocaine self-
administration (102,103). However, it has been shown that opioids indirectly
affect DA cell firing through inhibition of GABA interneurons in the VTA (104).
This disinhibition can result in enhanced DA release in the NAcc (105). Heroin
self-administration increases DA in the accumbens, and this has been argued to
be the mechanisms of action for heroin reinforcement (106).
Curiously, DA cells bodies in the VTA seem to be more important for heroin
self-administration than the DA innervation of the ventral striatum. Bozarth and
Wise (107) showed that 6-OH-DA lesions of the VTA impair the acquisition of
IV heroin self-administration. By contrast, 6-OH-DA–induced depletion within
of the NAcc has very little effect on heroin self-administration in spite of the fact
that 6-OH-DA such lesions dramatically reduce or abolish cocaine self-
administration (108,109). It appears that some, but not all, of the reinforcing
effects of opioids are mediated through an action on DA mechanisms.
Cannabinoids
The characterization of cannabinoid receptors in the brain has been an important
first step in identifying the site of action for the reinforcing effects of marijuana.
Two cannabinoid receptors (CB1 and CB2) have been identified to date. Both
are G protein–coupled receptors and function to inhibit adenylate cyclase. They
are acted on by endogenous cannabinoids and exogenous activators such as
marijuana. Figure 4-6 represents CB1 expression in the rat brain. As in humans,
the CB1 receptor is highly expressed in the brain and found in the basal ganglia,
hippocampus, cerebellum, cerebral cortex, and striatum (110). This expression
may explain some of the behavioral effects of marijuana (motor, memory, or
cognitive impairment; see Ref. 111). The CB2 receptor was once thought to be
only expressed in peripheral immune cells but has recently been identified in the
brain at low levels (112).
Figure 4-6 Cannabinoid receptor expression in the rat brain.
Areas with brightest colors indicate a greater expression.
Cannabinoid receptors are expressed in high numbers in the
cerebellum (Cer), hippocampus (Hipp), globus pallidus (GP),
external globus pallidus (Ep), and the substantia nigra pars
reticulate (SNr). Sp Cd, spinal cord. (Courtesy of Dr. Allyn
Howlett.)
Progress in identifying the brain mechanisms associated with the reinforcing

effects of cannabinoids has been hampered until recently by the lack of a good
animal model. Route of administration is a major influence on the reinforcing
effects of drugs, and smoking is the preferred route for marijuana use in humans.
Smoking, of course, is not an option for studying cannabinoid use in rats, and
there have been no reports of successfully training nonhuman primates to smoke
marijuana. Instead, attempts have been made to demonstrate IV self-
administration of Δ9-tetrahydrocannabinol (THC), the active ingredient in
marijuana, and other cannabinoid receptor agonists. Despite a good deal of
effort, early studies provided little evidence that rats would self-administer Δ9-
tetrahydrocannabinol (111), although self-administration of THC and
anandamide analogs has been reported in squirrel monkeys (113,114). More
success has been achieved with the synthetic CB1 receptor agonist WIN 55,212-
2, which has been shown to be self-administered by mice (115) and rats
(116,117).
The neurobiological investigation of cannabinoid self-administration is in
the early stages although it appears that both opioid and DA mechanisms may
interact with cannabinoid reinforcement (118–120).
NEUROANATOMY OF DRUG
ADDICTION
As discussed above, the acquisition and maintenance of substance use disorders
involves multiple cortical and subcortical brain regions. It also occurs on a
continuum wherein initial exposure leads to increased and compulsive drug
taking. This often occurs in the face of adverse consequences and at the expense
of more socially or biologically important behaviors. To understand how the
behavioral repertoire becomes subverted, it is necessary to consider the
structures involved in decision-making and in generating motivated behavior.
The research questions that can be addressed by using animal models are
necessarily different than those that can be asked with human subjects. Animal
studies have a number of advantages and are well suited for the investigation of
the site of action of drug reinforcement through the use of receptor agonists,
antagonists, and lesion techniques. Animal self-administration studies allow tight
control over many variables that could possibly affect the addiction process
including genetics, frequency of access, dosage, route of administration, and
drug history. Understandably, this type of control is unattainable in the
investigation of humans with addiction; however, human studies allow for the
examination of aspects of addiction that are uniquely human. Addiction is a
disease that lives in the real world and thus encompasses many different facets,
such as polydrug use, comorbidity with other disorders, predisposition, drug use
history, and environmental context. Thus, the literature on human unhealthy
substance use and addiction offers quite different insights.
Imaging technology has been a key tool in the investigation of the
neuroanatomy of addiction in human subjects. The two most widely used types
of functional imaging are positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI). These technologies have very different
temporal resolutions and lend themselves to assessing very different aspects of
brain function. PET uses a radioisotope that is introduced into the body and
binds to specific receptors, transporters, and enzymes. Specific ligands can be
visualized, thereby offering insights into drug distribution and changes in
receptor mechanism in vivo. fMRI offers much greater temporal and spatial
resolution. Changes in the fMRI signal can be assessed on the order of seconds
rather than minutes, making it possible to detect metabolic changes associated
with transient cognitive demands or craving states.
Early imaging studies asked the questions, “Where does cocaine act in the
brain, and how does it affect brain function?” One of the first imaging studies on
individuals addicted to cocaine was conducted by Volkow et al. (121) in 1988.
She found that individuals who chronically use cocaine have decreased relative
cerebral blood flow (as measured by PET) in the PFC. Volkow later showed
changes in metabolic activity (as measured by fluorodeoxyglucose), which
depended on the time since the last drug experience. An overall increase in
metabolic activity was observed in frontal brain regions during the first week of
withdrawal (122), whereas decreases in metabolic activity were found after
several months (123). PET has also been used to map the binding sites of
cocaine in the human brain. Fowler et al. (124) conducted the first of these
studies showing high cocaine binding in the corpus striatum in nondrug using
human subjects.
More recent work with PET has shown that striatal dopamine D2 receptor
binding is reduced in those who use cocaine (125), heroin (126), and
methamphetamine (127) and also in DSM-IV defined alcohol dependence (128).
This area of work is in good concordance with nonhuman primate PET studies
showing decreased D2 receptor availability in animals that are more susceptible
to the reinforcing aspects of cocaine (129,130).
fMRI studies have been used to examine transient drug states, such as drug
craving and the “rush” feeling associated with drug use. Much of the work in
this area has been done by giving cocaine-addicted subjects (because of ethical
limitations on giving drug-naive people cocaine) infusions of cocaine and other
stimulants while in the fMRI scanner. Breiter et al. (131) found that self-reports
of craving for the upcoming infusion of cocaine corresponded to increases in
activity in the NAcc and decreases in activity in the amygdala. He also observed
increases in the ventral tegmentum (VTA and substantia nigra), pons, basal
forebrain, caudate, and cingulate that correlated with self-reported feelings of
rush. Further work into drug craving has shown that drug-addicted individuals
have greater increases in brain activity in limbic areas and the PFC following the
presentation of drug-associated cues (such as pictures of drugs and drug
paraphernalia) when compared with nondrug users (132–134) and decreased
responsiveness when presented with nondrug reinforcers (eg, sexually evocative
cues) (135).
One brain area, the insula, has been recently recognized as having an
essential role in the detection of interoceptive cues. These cues can also provoke
powerful cravings for drugs and are a key component in the addiction process. A
recent study by Naqvi et al. (136) discovered that nicotine-dependent patients
with lesions to their insula reported disruption of smoking at a far greater
frequency than did patients with lesions to other brain areas. Furthermore,
smokers who acquired insula damage were more likely to quit smoking easily
and immediately and to remain abstinent. Remarkably, drug-associated cues can
produce limbic activation in individuals who use cocaine even when these
stimuli are not consciously perceived. Childress et al. (137) presented stimuli for
only 33 ms. Although this short presentation was too brief for the image to be
correctly identified, the drug-related stimuli nonetheless produced a strong
increase in activity in the ventral pallidum and amygdala. The intensity of this
response strongly predicted the magnitude of the subject’s affective response
when later shown visible versions of the same cues (137). These data suggest
that drug cues can stimulate drug craving even before there is conscious
awareness. Childress et al. (137) speculate that “by the time the motivational
state is experienced and labeled as conscious desire, the ancient limbic reward
circuitry already has a running start.” The imaging field now provides concrete
evidence of limbic involvement in drug craving that fits well with the wealth of
evidence for animal studies.
MOVING FORWARD
This chapter has focused on the alterations in brain structure and functional
activity associated with initial drug reinforcement and addiction. We have not,
however, addressed the changes in brain structure and function that may adapt
following extended abstinence. While this is beyond the scope of the present
chapter, there are many studies, which suggest that the limbic system is a critical
biomarker for abstinence (138–140). Additionally, as we attempt to bridge the
neurobiological findings from clinical and preclinical studies of chronic drug use
to abstinence, it will also be important to integrate the literature on behavioral
patterns that predict successful recovery. Through the integration of these
components, we will be much more likely to generate individually tailored
therapies, both pharmacological and behavioral, for those that find themselves
on this continuum of addiction, from vulnerable adolescents to treatment-seeking
individuals that recurrently relapse.
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CHAPTER 5
From Neurobiology to Treatment:
Progress against Addiction
Drew D. Kiraly and Eric J. Nestler
CHAPTER OUTLINE
Introduction
Blockade of Drug Targets
Mimicry of Drug Action
Blockade of the Addiction Process
INTRODUCTION
In terms of lost lives and productivity, drug addiction remains one of the most
serious threats to our nation’s public health. Addiction can be defined as the loss
of control over drug use or the compulsive seeking and taking of a drug
regardless of the consequences. Available treatments for addiction remain only
somewhat effective for most individuals (1,2). Consequently, there is intense
interest in better understanding the neurobiology of addiction in the hope that
such knowledge will eventually lead to more effective treatments.
The diverse types of drugs that lead to addiction share no similarities in
chemical structure, and yet they produce similar behavioral syndromes.
Considerable progress has been made in understanding how drugs cause
addiction. The initial protein targets for virtually all drugs are known (Table 5-1)
(3). Also, several circuits in the brain, containing these drug targets, have been
shown to mediate the addicting actions of drugs (3–5). Most attention has been
given to the nucleus accumbens (a part of the ventral striatum) and its
dopaminergic input from the ventral tegmental area of the midbrain as key
substrates for these drug effects. Other brain regions interact with this circuit,
including several regions of prefrontal cortex, amygdala, hippocampus, and
hypothalamus, to name a few.
TABLE 5-1 Acute Actions of Some Drugs of Abuse

aActivity at μ (and possibly) δ receptors mediates the reinforcing actions of opioids; κ receptors mediate
aversive actions.
bCocaine and amphetamine exert analogous actions on serotonergic and noradrenergic systems, which
may also contribute to the reinforcing effects of these drugs.
cGi couples D -like dopamine receptors, and Gs couples D -like dopamine receptors, both of which are
2 1
important for dopamine’s reinforcing effects.
dEthanol affects several other ligand-gated channels and at higher concentrations voltage-gated channels
as well. In addition, ethanol is reported to influence many other neurotransmitter systems, including
serotonergic, opioidergic, and dopaminergic systems. It is not known whether these effects are direct or
achieved indirectly via actions on various ligand-gated channels.
eActivity at CB receptors mediates the reinforcing actions of cannabinoids; CB receptors are expressed
1 2
predominantly in the periphery but may also be involved in central actions. Endogenous ligands for the
CB1 receptor include the arachidonic acid metabolites, anandamide, and 2-arachidonylglycerol.
Data from Nestler EJ. Molecular basis of neural plasticity underlying addiction. Nat Rev Neurosci.
2001;2:119-128.
These brain structures are referred to as reward pathways, which are very old
from an evolutionary point of view and which presumably evolved to mediate an
individual’s responses to natural rewards, such as food, sex, and social
interaction. Drugs activate these reward pathways, in the absence of natural
rewards, with a force and persistence not seen under normal conditions. Over
time, repeated drug exposure causes adaptations in the brain’s reward pathways,
which seem to have two major consequences. First, during periods of active drug
use or shortly after ceasing drug intake, the ability of natural rewards to activate
the reward pathways is diminished, and the individual experiences depressed
motivation and mood. Taking more drug is the is the most rapid means by which
a person with addiction to feel “normal” again. Second, drug use causes long-
lasting memories related to the drug experience, such that even after prolonged
periods of withdrawal (months, years), stressful events or exposure to the drug or
to drug-associated cues can trigger intense craving, and in many cases relapse, in
part by activating the brain’s reward pathways. Roughly half of the risk for
addiction is genetic, although few specific genes that constitute this risk have to
date been identified (6–8). While a great deal of effort is aimed at identifying
these specific genes, it is likely that the vast majority of addiction risk genes
exert very small effects on their own and that an individual’s composite risk for
addiction is mediated by perhaps hundreds of genetic variations. As these risk
genes are identified, it will be important to establish the mechanisms by which
diverse nongenetic factors interact with the genes to influence the development
of an addictive disorder.
Addiction should be viewed as distinct from physical dependence, wherein
individuals become physically sick when drug administration ceases (3).
Physical dependence per se is neither necessary nor sufficient to cause addiction:
some drugs do not cause appreciable physical dependence, and some
medications used in general medicine cause physical dependence but are not
addicting (eg, β-adrenergic antagonists such as propranolol). Moreover, physical
dependence and withdrawal syndromes for drugs and nonabused medications are
largely mediated by different central nervous system regions than those
important for addiction. Nevertheless, some of the clinical progress in the
addiction field has come from improved methods of treating the physical
dependence and severe withdrawal syndromes associated with opioids and
alcohol (1). Knowledge of opioid action on opioid receptors at a cellular level
led to the development of several medications now used to treat opioid
withdrawal. Buprenorphine is a partial agonist at the μ-opioid receptor and is
used to treat withdrawal from opioids (9,10). Clonidine, an α2-adrenergic
agonist, produces cellular effects similar to opioid receptor activation and
dampens many of the physical signs and symptoms of opioid withdrawal in
humans (9,10). These approaches are in striking contrast to the extremely painful
“cold turkey” method that characterized opioid withdrawal management a
generation ago. Similarly, based on the knowledge that alcohol and sedative–
hypnotics both facilitate gamma-aminobutyric acid (GABA) receptor function,
benzodiazepines (or other medications that modulate GABA systems) are now
used routinely to prevent the life-threatening sequelae of alcohol withdrawal.
The impact of these advances, however, is limited because treatment of
physical dependence and withdrawal does not target the core clinical symptoms
of addiction—namely, drug craving and relapse to drug use even after prolonged
abstinence. Unfortunately, treatment of the core symptoms of addiction has
proved much more difficult than is treatment of physical withdrawal syndromes.
BLOCKADE OF DRUG TARGETS

Approaches pursued to date can be divided into several categories, including
blockade of drug targets, mimicry of drug action, and blockade of the addiction
process (Fig. 5-1). The most straightforward strategy is to block the drug from
getting to its target. Such a treatment agent should have the additional
requirement of not affecting that target on its own. The best example of this
approach is naltrexone (9,10). In theory, naltrexone is inactive in the absence of
an opioid but blocks the ability of opioids to produce their many effects,
including addiction. Indeed, naltrexone can be used to treat opioid addiction but
has its limitations. Naltrexone is in fact not inactive in the absence of exogenous
opioids. This is because the drug blocks the actions of the body’s endogenous
opioid peptides (enkephalin, endorphin, and dynorphin); this can cause negative
emotional effects (such as depressed mood) in some individuals, which can
reduce patient compliance (9,10). As a result, naltrexone is mostly effective for
highly motivated individuals with opiate addiction, such as those patients whose
employment is dependent on drug compliance. Based on animal studies showing
that alcohol’s and nicotine’s addicting actions are mediated in part via activation
of endogenous opioidergic neurons (Fig. 5-1), naltrexone has been used to treat
addiction to these drugs. Some efficacy is observed clinically, but the effects of
naltrexone are relatively small in magnitude and effective for a subset of patients
only (11). Naltrexone is also being studied as well for the treatment of addiction
to cocaine and other psychostimulants.
Figure 5-1 General strategies used to treat drug addiction or

associated physical withdrawal syndromes. A dendritic spine
of a nucleus accumbens (NAc) neuron and its innervation by
terminals of glutamatergic (Glu), dopaminergic (DA), and
opioidergic (Op) neurons are shown. 1: One approach is to
block the ability of a drug to reach its initial protein target:
for example, naltrexone’s antagonism of opioid receptors
(OR) or a hypothetical drug that interferes with cocaine’s
actions on the dopamine transporter. Not depicted is the use
of immunological methods (such as a cocaine or nicotine
vaccine) to prevent a drug from entering the brain. 2: A
second approach is to mimic drug action: for example,
sustained activation of OR by methadone, or activation of DA
receptors (DAR) by various agonists or partial agonists. 3: A
third approach is to influence the process of addiction: for
example, via perturbation of Glu receptors (AMPA, NMDA,
metabotropic receptors) or a host of postreceptor signaling
proteins (such as those involved in the cAMP, calcium, and
MAP kinase pathways and in the regulation of gene
expression—ΔFosB, CREB, or NFκB) that have been
implicated in addiction. (From Nestler EJ. Molecular basis of
neural plasticity underlying addiction. Nat Rev Neurosci.
2001;2:119-128; Hyman SE, Malenka RC, Nestler EJ. Neural
mechanisms of addiction: the role of reward-related learning
and memory. Annu Rev Neurosci. 2006;29:565-598; Robison
AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of
addiction. Nature Rev Neurosci. 2011;12:623-637.)
A related approach is to develop a “vaccine” for a drug, which would prevent it

from binding to its initial target. One major effort along these lines has been
focused on cocaine. The most important mechanism of action of cocaine is
inhibition of presynaptic dopamine transporters (Fig. 5-1). The goal for
treatment would be to prevent cocaine’s binding to the transporter without
affecting the transporter’s normal functioning. Despite intense effort, suitable
pharmacological treatments have not yet been developed, which prompted the
focus on a vaccine. By immunizing an individual with cocaine coupled to a
carrier, it has been possible to generate immunity in animals (12,13). When the
animals are subsequently challenged with cocaine, the drug’s clearance is
increased by peripheral antibodies, its penetration into the brain is decreased,
and its behavioral effects are attenuated. Cocaine vaccines are now in clinical
development and could prove useful, but there are several potential drawbacks.
First, cocaine already has a very short half-life. It is not clear whether increased
clearance made possible by active immunity would have a functionally
meaningful effect in humans. Second, a cocaine vaccine would not be active
against other stimulants (eg, amphetamine, methamphetamine), and those who
used cocaine could easily switch to another drug. There have been several
clinical trials of cocaine vaccines to date, and while early trials showed promise
more recent studies have been negative. The use of a cocaine vaccine also raises
important ethical considerations, such as the potential loss of privacy (the
presence of such antibodies would “mark” a person with addiction) and whether
vaccine administration could be legally mandated in patients with drug-related
convictions (14). An alternative to such an active vaccine would be passive
immunity, also under investigation, where a person using cocaine would be
injected at set intervals with anticocaine antibodies. Similar efforts are under
way to generate a vaccine toward nicotine, which is in early clinical trials
(12,13).
Cannabinoids, the active ingredients in marijuana, act through the
stimulation of CB1 receptors. Moreover, there is evidence that other drugs of
abuse (eg, opioids, alcohol) may produce part of their addicting effects via the
activation of endogenous cannabinoids in the brain (see Table 5-1) (15). This has
led to the speculation that CB1 antagonists may be of use in treating various
addiction. Rimonabant is a CB1 inverse agonist—it functions as an antagonist,
earlier approved in Europe for the treatment of obesity. Its potential efficacy in
treating addiction remains unknown. An important cautionary note is that use of
rimonabant is associated with the onset of depressive symptomatology in some
patients, including the incidence of suicide, which led to withdrawal of its
approval in Europe and severely limited further exploration of this
pharmacological approach (16).
MIMICRY OF DRUG ACTION

Contrary to efforts to block drug effects, there has been considerable interest and
progress in treating addiction by mimicking drug action. This approach is based
on the notion that blocking drug targets, as mentioned previously, would leave
the addicted person with an altered, addicted brain and the intense drug craving
it produces. In contrast, by activating drug targets, it might be possible to
partially alleviate this drug craving and allow the brain to slowly recover. A
critical aspect of this approach, and presumably of brain recovery, is to use long-
acting medications that would do more than simply mimic a drug; the drugs
would need to do so in a sustained manner, thereby avoiding the rapid on and off
phases of repeated drug exposure. Although the effectiveness of drug mimicry
has been documented clinically, it is poorly understood at the neurobiological
level.
The best-established example of this approach is methadone, a long-acting
opioid receptor agonist. The only difference between methadone and other
opioids is its long half-life, which means that, at the proper dose, patients
receiving methadone have a modest level of sustained activation of opioid
receptors. This enables patients to avoid the daily extremes of “highs” on drug
administration and withdrawal as the drug effects wear off. This, in turn, enables
the patients to return to a more normal life of steady work and social
interactions. Decades of experience have documented the safety and efficacy of
methadone in the treatment of a subset of patients with opioid use disorder,
although it is difficult to predict which individuals will respond best (17,18).
Another long-acting opioid agonist, levo-alpha-acetylmethadol, was used
similarly, although it causes cardiac side-effects in some patients and was
withdrawn from US use in 2003. A variation in this theme is buprenorphine
(10,19). As a high-affinity partial agonist, buprenorphine binds to opioid
receptors and produces a mild agonist effect. Higher doses of the drug do not
produce stronger effects because the ability of buprenorphine to activate the
receptor is intrinsically low. However, buprenorphine, bound to the receptor at
high affinity, can block the effects of opioid drugs, which limits the ability of a
person with an addiction to obtain a drug “high” during treatment. Despite the
clear utility of this general approach, and considerable success in many patients,
there remains significant concern toward methadone, buprenorphine, and related
treatments, because the addicted person is still being exposed to opioids and may
be vulnerable to deleterious effects of these medications.
Another example of the mimicry approach is the use of nicotine patches or
chewing gum to treat tobacco addiction. The resulting sustained release of low
levels of nicotine can dampen craving for cigarettes in some patients long
enough to help the individuals quit smoking (20). However, such approaches are
not effective in most smokers, perhaps because of the very stable nicotine-
induced changes in the brain that sustain the addiction. Perhaps agonists or
partial agonists selective for particular nicotinic cholinergic receptors in the
brain that mediate nicotine addiction would be more effective than low levels of
nicotine itself. Indeed, one such nicotinic partial agonist, varenicline, is approved
widely around the world for treatment of nicotine addiction, and clinical
experience supports effectiveness in smoking cessation in a subset of patients
(20,21).
A final example of mimicry is the use of a stimulant to treat stimulant
addiction. For example, amphetamine or related drugs show some promise in
treating cocaine addiction, although this clinical approach remains controversial
(22). A related notion is the utilization of dopamine receptor agonists or
antagonists to treat stimulant or other addiction. Mentioned briefly earlier is the
important role of dopamine in drug addiction. Stimulation of dopaminergic
transmission in the nucleus accumbens and elsewhere seems to be the most
important mechanism of stimulant action and contributes to the actions of all
other drugs of abuse as well (Fig. 5-1) (3–5). Thus, activation of opioid,
cholinergic, or cannabinoid receptors increases dopaminergic transmission in
these brain regions. Based on this knowledge, there has been intense effort to use
dopamine receptor antagonists and agonists in the treatment of addiction. The
goal is to develop agents that regulate the general process of addiction, which
might be equally effective for all drugs of abuse. Use of dopamine antagonists is
based on the notion that inhibition of drug effects would limit drug use, whereas
use of dopamine agonists is based on the notion that mimicry of drug effects
would be more efficacious. The former approach has not been promising.
Although dopamine receptor antagonists can block acute drug effects, there is no
evidence that they limit drug craving or self-administration in the long term.
They may even make animals and humans more sensitive to drugs via adaptive
increases in dopamine receptor signaling efficacy. In contrast, there is some
promise for the use of D1 receptor agonists and D2 receptor partial agonists,
which dampen cocaine craving and relapse in animal models (23,24). Studies in
humans are a high priority but are limited by the lack of availability of suitable
compounds for human use.
BLOCKADE OF THE ADDICTION

PROCESS
A great deal has been learned over the past decade about the changes that drugs
cause in the brain’s reward pathways to produce addiction (3,25). Current
research aims to exploit this information for the development of more effective
treatments. However, efforts in this realm are almost entirely speculative and
must be viewed with skepticism. It is clear, for example, that glutamatergic
innervation (from prefrontal cortex, amygdala, and hippocampus) is crucial for
the normal activity of the nucleus accumbens and ventral tegmental area.
Moreover, drugs alter levels or activity of several types of glutamate receptors or
other protein components of the glutamatergic synapse within these regions
(26,27). This raises the possibility, untested to date in humans, that drugs aimed
at glutamatergic mechanisms—for example, specific types of glutamate
receptors or transporters—might be of use in the treatment of addiction. Given
the prominent role of glutamatergic mechanisms in learning and memory, and
increasing evidence that important aspects of addiction can be viewed as a form
of memory, it is possible that glutamatergic agents, given in conjunction with
behavioral therapies, might be most efficacious at fundamentally altering
addictive behavior. For example, we now know that extinction of a memory is
not the passive process of undoing that memory, but rather the formation of an
active new memory that supersedes the old one. Hence, a drug that enhances
glutamatergic transmission and, therefore, new memory formation, given in
concert with behavioral extinction trials, might be a novel approach to treating
addiction-related memories that are thought to underlie aspects of craving and
relapse (28,29).
In a similar way, numerous other neurotransmitter, neuropeptide, and
neurotrophic factor systems are altered by drugs and, in turn, modulate drug
effects in laboratory animals: GABA, neuropeptide Y, corticotropin-releasing
factor, serotonin, norepinephrine, melanocortins, and brain-derived neurotrophic
factor, to name just a few (3,30). For example, several drugs aimed at
components of GABAergic synapses are under evaluation for the treatment of
addiction (31). As these effects are better defined in animal models, and putative
treatment agents suitable for human investigation are developed, these
mechanisms can be tested more definitively in clinical populations.
Drug addiction also involves adaptations at postreceptor, intracellular
signaling cascades, including alterations in gene expression (3,25). Moreover,
modification of particular signaling proteins can have dramatic effects on an
animal’s responses to drugs. Examples include several proteins that regulate the
function of G protein–coupled receptors: G proteins, G protein–receptor kinases,
arrestins, and regulators of G protein signaling proteins (32). Because the acute
targets of many drugs of abuse are G protein–coupled receptors, it is possible
that agents affecting these modulatory proteins could exert interesting functional
effects on the receptor systems so as to treat aspects of addiction. Similarly,
given the evidence for an important role of the cyclic adenosine monophosphate
(cAMP) pathway in addiction (3,25) and of the transcription factor ΔFosB (33),
it is conceivable that novel agents directed against protein components of these
pathways (such as phosphodiesterase inhibitors, which would enhance cAMP
function) might warrant investigation as clinical treatments. Still another
example is inhibitors of histone deacetylases (HDACs), enzymes that regulate
gene expression by acetylating nearby histones. Recent evidence demonstrates
that manipulation of specific HDACs, or of several other chromatin-modifying
enzymes, in the brain exerts a dramatic effect on drug-elicited behaviors (34).
Drug discovery efforts should, of course, focus on subtypes of these intracellular
signaling proteins that are highly enriched in the brain’s reward pathways and
would therefore represent potentially viable medication targets.
One of the central problems in approaching addiction is that truly effective
treatments are not yet available. Thus, it is impossible to know what types of
treatment are theoretically possible. For example, before the advent of
antidepressant medications, there was considerable debate about the nature and
magnitude of improvement possible with chemical treatments. By analogy, the
addiction field now aims to identify medications that dampen drug craving or
reward without interfering with motivation for natural rewards. Only as putative
treatment agents are developed and tested in animals and humans will insight
into the feasibility of this aim become available.
Perhaps an even greater obstacle in the development of new treatments for
addiction is the relative lack of interest by the pharmaceutical industry. This
problem has many roots, including the perceived stigma of addiction as well as
the presumption that markets for addiction treatment agents might be too small.
The latter would appear to be a major miscalculation by the industry. Experience
tells us that the size of many markets only becomes apparent when truly
effective treatments are available. Antidepressants, now a worldwide market of
more than ~$15 billion, are a case in point. By analogy, treatment agents that can
correct compulsive behavior toward drug rewards, if they can be developed,
would represent enormous successes, given their potential to treat not only drug
addiction but addiction to nondrug stimuli, such as gambling, food, and sex,
which are mediated in part by similar mechanisms. Such treatments could be
highly successful and offer dramatic improvement in public health.
ACKNOWLEDGMENTS
Preparation of this review was supported by grants from the National Institute on
Drug Abuse. Earlier versions of this chapter were adapted with permission of the
publisher from Nestler EJ. From neurobiology to treatment: progress against
addiction. Nat Neurosci. 2002;5(Suppl):1076-1079. © 2002, Nature
Neuroscience, New York, NY.
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CHAPTER 6
Clinical Trials in Substance-Using
Populations
Frank Vocci
CHAPTER OUTLINE
Introduction
Elements of a Clinical Trial
Types of Clinical Trials
Features of Clinical Trials
The Research Question Dictates Various Aspects of Trial Design
Outcome Metrics Used in Clinical Trials
Monitoring and Quality Control
Reporting Results in a Journal Article
Conclusions
INTRODUCTION
Clinical trials play an important role in the evaluation of interventions designed
to prevent, assess, treat, and educate in the field of addiction medicine. The U.S.
National Institutes of Health (NIH) defines a clinical trial as “A research study in
which one or more human subjects are prospectively assigned to one or more
interventions (which may or may not include placebo or other control) to
evaluate the effects of those interventions on health-related biomedical or
behavioral outcomes.” This chapter contains general information on human
subjects in clinical trials as well as comments on behavioral and
pharmacotherapy trials in substance-using populations. Reference will be made
to the published literature of trials in substance-using populations as illustrative
examples of the designs and outcomes being discussed. NIH trial requirements
and Food and Drug Administration (FDA) regulations and guidance documents,
especially with clinical trials involving pharmacological interventions, will be
noted so the reader can develop an appreciation for trial designs, outcome
measures, and clinical trial evidence needed to secure medication approval from
the FDA.
ELEMENTS OF A CLINICAL TRIAL

Clinical trials are conducted within a legal–regulatory framework. A proposed
clinical trial must be reviewed and approved by an institutional review board
(IRB) prior to commencement
(ie, http://www.fda.gov/RegulatoryInformation/Guidances/ucm126420.htm#IRBOrg
The role of the IRB is to protect the rights and welfare of human subjects. A
principal investigator and co-investigator will submit drafts of the following
materials for review: a detailed protocol; surveys, questionnaires, and rating
scales that will be used in the trial; an informed consent document; advertising
material; qualifications of the investigators; evidence of certification of training
in human research for the research staff; and financial disclosure forms for the
determination of potential conflict of interest. In trials involving investigational
or approved medications, the investigators will also submit evidence of
investigational new drug (IND) approval from the FDA, FDA 1572 forms, the
investigator’s brochure or package insert, the data and safety monitoring plan, or
the composition of the Data and Safety Monitoring Board (DSMB, if
applicable).
The study protocol contains the following elements: the primary and
secondary objectives of the study; inclusion/exclusion criteria; recruitment
strategies and participant discontinuation criteria; information on the dosage
form, administration schedule, and duration of pharmacotherapy in a medication
trial or type, intensity, and duration of behavioral therapy in a behavioral
intervention trial; concomitant medications or other treatments allowed (if any);
the outcome measures; type and frequency of efficacy and safety assessments;
procurement, handling, shipping, and assay of biospecimens; justification of the
sample size to be recruited; the proposed statistical analyses; collection of
adverse event data and reporting of safety issues to the IRB and other regulatory
agencies; participant and trial stopping rules; interactions with the IRB and
DSMB; the informed consent process; information on confidentiality of
participant information, including certificates of confidentiality that are usually
obtained when working with substance-using populations; data handling and
data management procedures; and publication and data sharing intentions. A
protocol is considered to be a “living document.” Changes to a protocol may be
made to enhance the safety of the trial participants, for example, lowering the
maximum dose or duration of therapy due to adverse events observed in the trial.
Changes may also be made to the statistical analysis plan prior to the opening of
the trial data set. The NIH has developed a protocol template that they expect
prospective grantees to use when filing grants to perform clinical trials (1). The
template outline meets the standards elucidated in the International Conference
on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice, and
Consolidated Guidance (ICH-E6). Thus, the template is acceptable to the FDA
for developing protocols to determine the safety and efficacy of medications,
including those for treating substance use disorders (SUDs). Details regarding
individual studies and the totality of studies necessary for approval by the FDA
of a new medication are usually discussed in a series of meetings with the FDA
along the medication development pathway.
The informed consent document, which in most instances is a written
document, contains the following elements that are detailed in 45 Code of
Federal Regulations 46.16: a statement that the trial involves research; the
purpose of the research and the expected duration of the participant’s
involvement; the procedures to be followed and identification of any procedures
considered experimental; a description of the risks; a description of the potential
benefits to the participants and possibly others; a disclosure of alternative
treatments; a statement of the extent of confidentiality of the participant’s
records; an explanation as to whether any compensation or treatment is available
if an injury occurs; an explanation as to whom to contact in the event of
questions related to the research and the participant’s research rights and contact
information in the case of a research-related injury; and a statement that
participation is voluntary and the participant can withdraw from the trial at any
time without penalty or loss of benefits. Additionally, other elements may be
added to the consent form, for example, a statement that the treatment may
involve unforeseeable risks either to the participant or fetus, if the participant
becomes pregnant, circumstances under which the investigator may discontinue
the participants from the trial; additional costs that the participant may incur
from trial participation; consequences of withdrawal and procedures for orderly
termination; a statement that new findings that may affect the course of the
research and participant’s willingness to continue will be provided; and the
number of expected trial participants to be enrolled. For example, a tapering
regimen for a medication that should not be abruptly discontinued will be
included in the consent form in the case of a participant’s withdrawal from the
trial.
The investigator or his/her co-investigators describe the consent form to the
prospective participant and obtain their written consent. The prospective
participant must not be under the influence of alcohol or drugs at the time
consent is obtained. A written quiz may be given to ensure that the participants
understand the purpose of the study and their right to withdraw at any time
without prejudice. A copy of the signed consent form is given to the trial
participant.
There are additional requirements for conducting research in prisoner
populations (45 CFR 46.301–306). For example, the majority of the IRB
members must not have any association with the prison(s) involved; the IRB
must have a prisoner or a prisoner representative; and the risks involved must
not be greater than those that would be acceptable to nonprisoner volunteers.
The Secretary of Health and Human Services has delineated the types of
research that can be carried out with prisoners, for example, alcoholism and drug
addiction, and, following IRB approval, must approve each study. The approval
for prisoner studies has been delegated to the Office of Human Research
Protection in the Office of the Secretary of Health and Human Services.
TYPES OF CLINICAL TRIALS

There are three main types of clinical trials that evaluate the impact of an
intervention in a clinical population: efficacy, effectiveness, and comparative
effectiveness (2). These trials are on a continuum of control in design and
external validity or generalizability to the patient population with the disorder
with efficacy trials being the most restrictive and controlled but least
generalizable and effectiveness trials having high generalizability. Efficacy can
be defined as the performance of an intervention under ideal and controlled
circumstances, whereas effectiveness refers to its performance under “real-
world” conditions. Each type of clinical trial will be discussed in turn.
Efficacy Trials
Efficacy trials (phase II) compare an intervention to another treatment in a
rigorous, controlled design that is optimized for detection of an efficacy signal.
For example, in the initial phase II trial evaluating efficacy of varenicline for
treatment of an alcohol use disorder (AUD) (3), the following
inclusion/exclusion criteria usually found in phase II trials were noted: the
participants met criteria for diagnosis of an AUD but do not have other SUDs;
participants did not have co-occurring psychiatric or medical comorbidities; and
concomitant medications affecting the central nervous system were not allowed.
The following features typical of a phase II trial were noted: participants were
randomized to the medication or control treatment (placebo); neither the
investigators nor the participants knew the treatment assignment (double
blinding); the investigators were highly trained in the delivery of the
intervention; the doses of the medication were fixed after the initial titration, and
the duration of treatment (8-12 weeks) was shorter than a full treatment course;
behavioral treatment was minimized and consisted of participants viewing a
computerized bibliotherapy platform derived from the Rethinking Drinking
program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA);
the primary efficacy end point was defined as percent heavy drinking days
measured weekly; secondary measures of drinking, craving for alcohol,
consequences of drinking, cigarette use, and quality of life outcome measures
were defined and assessed; and adverse events were ascertained at clinic visits
and during telephone interviews. The advantages of such a design are that it has
high internal validity, minimizes potential bias through the random assignment to
treatment arms, has a homogenous study population, optimizes efficacy signal
detection, and allows investigators to determine rating scales that are sensitive to
the effect of the medication. The disadvantages are that it lacks external validity
or generalizability to patients most likely to get the medication, and given the
usually stringent exclusion criteria, it can underestimate the safety profile of the
medication in the ultimate patient population for which it is intended.
Efficacy trials (phase III): Double-blind, placebo-controlled trials are also
conducted in phase III with several differences noted between the two phases: a
larger sample size is enrolled; there are fewer exclusion criteria so that the study
population is more similar to patients seen in clinical practice; a longer duration
of treatment is administered, sometimes exceeding 1 year of dosing; fixed
dosing, flexible dosing regimens, and titration schemes can be evaluated;
concomitant medications may be allowed; and behavioral treatments may mimic
the standard of care so that placebo-treated participants are treated ethically. The
larger sample size allows the assessment of benefit and risk in the population
most likely to get the medication “in the real world” and improves the chances of
discovering serious adverse events that occur at low frequency in the patient
population. The FDA and other regulatory agencies usually request a study
census of 300-600 participants in order to assess event rates that occur in the
0.5%-5% range (ICH E1 guideline). Studies with 100 participants dosed at levels
intended for clinical use for a minimum of 1 year are acceptable to the regulatory
agencies to allow indefinite prescribing in the product label of the medication.
The multicenter phase III trial of buprenorphine and buprenorphine/naloxone
versus placebo serves as an illustration of a phase III trial (4). The study was
conducted in two parts: initially, 326 opioid-dependent persons were enrolled at
eight sites and randomized to fixed doses of buprenorphine tablets (16 mg),
buprenorphine/naloxone tablets (16/4 mg), or placebo for 1 month. Participants
came to an outpatient clinic Monday through Friday and received take-home
doses for the weekend. Participants received HIV counseling and up to 1 hour of
counseling per week. After 1 month, the second part began with all remaining
participants (N = 279) administered buprenorphine for 2 days up to a maximum
of 12 mg and then switched to buprenorphine/naloxone in an open-label fashion
for an additional 11 months. Four additional clinics admitted 193 new
participants for 11 months of dosing. Thus, 472 participants received open-label
buprenorphine/naloxone, up to 24/6 mg daily dose, for 11 months, resulting in
92,930 days of exposure to the medication. For the first 2 weeks, participants
received their medication at the clinic in the same fashion as part one.
Thereafter, they could get a 10-day take-home supply of medication with each
clinic visit. Two hundred sixty-one (261) participants completed 6 months of
dosing with buprenorphine/naloxone. This trial contained multiple elements of a
phase III trial: a large sample size, collection of safety data during 1-year
duration of dosing, fixed dosing and doses that are titrated, allowance for take-
home medication, random collection of urine samples twice a month, results of
the urine tests during part two of the trial were available to investigators, and
multiple outpatient settings where the research was conducted.
In some circumstances, large sample, simple trials (LSSTs) are conducted in
phase III. In these trials, participants are randomized to treatment groups and are
focused on an adverse event of interest, for example, hepatotoxicity that is not
resolved with the safety database that has been accumulated in the development
of a medication.
Phase IV Trials
LSSTs can also be conducted in phase IV (postapproval) as part of a
commitment to evaluate a lingering toxicity concern (FDA premarket safety
assessment guidance). Such was the case with the approval of buprenorphine and
buprenorphine/naloxone for the management of DSM-IV–defined opioid
dependence. The FDA requested a postmarketing study of the hepatic effects of
buprenorphine. The study was conducted by the Clinical Trials Network (CTN)
of the National Institute on Drug Abuse (NIDA). Twelve hundred sixty-nine
opioid-dependent participants were randomized to buprenorphine/naloxone or
methadone; their serum transaminase levels were followed for 32 weeks (5).
Neither medication was associated with liver damage during the initial 6 months
of the study.
Effectiveness Trials
Effectiveness trials assess the impact of an effective therapy in real-world
settings. Effectiveness trials are usually conducted in phase IV by practicing
clinicians in a heterogeneous population that often has multiple comorbidities.
The protocols are usually more flexible with regard to dosing, and concurrent
treatment modalities may be permitted. Participants can be randomized to a
treatment arm, but the comparison group is often a “treatment-as-usual” group as
opposed to a placebo-controlled group (2). Effectiveness trials evaluate factors at
the level of patient, provider, and system that may influence the efficacy of a
therapy. Contingency management reinforces a target behavior, either abstinence
from drug use or clinic attendance. An example of a behavioral effectiveness
study is the addition of contingency management, that is, voucher incentives for
abstinence from cocaine or amphetamines added onto TAU versus TAU (6).
Participants randomized to the voucher incentive group remained in treatment
longer, had fewer positive urines for stimulants and alcohol, and attended more
counseling sessions than the TAU group (all p = 0.02). An example of an add-on
behavioral therapy to pharmacotherapy trial is the addition of cognitive
behavioral therapy to physician management of 141 buprenorphine/naloxone-
treated patients in a primary care clinic (7). Following randomization to baseline
medical management or medical management plus cognitive behavioral therapy,
patients were followed for 24 weeks. The self-reported reduction in opioid use
during the trial was similar between the two groups (p = 0.96). There was also
no difference reported between the groups in terms of maximum consecutive
weeks of abstinence (p = 0.84). Another example of an add-on pharmacotherapy
is a multicenter effectiveness trial of extended-release naltrexone versus TAU.
The trial was designed to evaluate whether extended-release naltrexone reduced
the likelihood of an opioid relapse event in a community-dwelling, criminal
justice population with a history of opioid dependence (8). Participants were
randomized to extended-release naltrexone with TAU, consisting of brief
counseling and referral to treatment programs, or TAU. The percentage of
participants experiencing relapse, defined as evidence of >10 days of opioid use
in a 28-day period, was lower in the extended-release naltrexone group (43% vs.
64%, p = 0.001) (9). Moreover, there were no overdose events in the extended-
release naltrexone group, while seven overdose events were recorded in the TAU
group (p = 0.02).
Comparative Effectiveness Studies

Comparative effectiveness studies are a subset of effectiveness studies and have
been defined as “the generation of and synthesis of evidence that compares the
benefits and harms of alternative methods to prevent, diagnose, treat, and
monitor a clinical condition or to improve the delivery of care (10).” The
purpose and setting are nearly identical to the purpose and setting of
effectiveness studies although the comparator may be a different modality of
treatment, for example, medical versus surgical management of coronary artery
disease. Rawson et al. (11) compared the effects of 16 weeks of contingency
management (CM), cognitive behavioral therapy (CBT), and the combination of
the two therapies (CM + CBT) in 171 individuals with DSM-IV–defined
stimulant dependence. Retention was superior in the CM and CM + CBT groups
compared to the CBT group, p < 0.02. The percentage of study participants
achieving 3 weeks of continuous abstinence was also higher in the CM and CM+
CBT groups compared to the CBT group (60%, 69.5% vs. 40%, respectively, p,
0.0001). None of the treatments were superior to the others at the 26 and 52
week follow-up time points. Similar results were reported in a study of CM and
CBT in treating cocaine using methadone-maintained patients (12). A
pharmacotherapy example of a comparative effectiveness trial is the comparison
of sublingual buprenorphine/naloxone versus extended-release naltrexone in the
NIDA CTN (ClinicalTrials.gov # NCT02032433). Design considerations
involved in evaluating these two different medications have been examined (13).
To date, 772 participants have been enrolled. The primary outcome measure is
the estimated time to relapse. Secondary outcome measures include abstinence
from opioids over time, alcohol and other drug use, withdrawal complaints,
adverse events, cognitive function, economic costs, and cost-effectiveness and
cost–benefit.
FEATURES OF CLINICAL TRIALS

Randomization
As described above, clinical trials often use a randomization scheme to assign
participants to different treatment arms. The randomized clinical trial (RCT) is
considered to be the “gold standard” trial design in the assessment of efficacy
(14). The purpose of randomization is to avoid selection bias. Randomization
schemes used in SUD trials have been described (15). Randomization can be as
simple as assigning each participant to a treatment arm with equal probability
although this can lead to imbalances in treatment assignment. The most common
randomization method used is the stratified permuted block, which allows for
balancing of covariates across treatment arms (14). Block sizes can be varied to
minimize the possibility of the investigators deducing the randomization scheme.
More complex randomization schemes such as urn randomization attempt to
reduce differences in baseline characteristics by adjusting the probability of
assignment to a treatment arm based on the degree of current treatment
imbalance (16, 17). Irrespective of the type of randomization scheme used,
differences in baseline characteristics of the groups may occur. The degree of
influence of the baseline differences on treatment outcome may be estimated
using propensity scoring (18).
Blinding
“Blinding” refers to the process of concealment of the treatments or group
assignments (19). A single-blind protocol conceals the treatment assignment
from the participant but not the investigator. The more common double-blind
design masks treatment assignment from both the investigator and the study
participant. In placebo-controlled, double-blind studies, the active medication
and placebo should appear identical in appearance and taste. Since most
medications are bitter, placebo capsules or tablets can match bitterness by adding
denatonium benzoate (20).
Some studies compare two completely different looking medications under
blinded conditions. In this instance, participants receive the active medication of
one treatment and a placebo treatment of the comparator drug in a balanced
fashion. This type of blinding is called by the term “double dummy.”
It is not possible to mask treatment assignment in trials comparing different
psychosocial therapies. In these types of trials, a new psychosocial therapy is
usually compared to an established therapy.
Sample Size, Power, and Effect Size

All clinical trials should have a sufficient sample size to detect treatment
differences. The estimation of the sample size required for a clinical trial
assessing superiority of a medication versus placebo is based on the
characteristics of the population under study, whether there are data from clinical
trials in this population suggesting a drug–placebo difference and how variable
the difference is across studies and statistical considerations, that is, α, the
probability of concluding a difference exists between groups when one does not
(false-positive rate also known as type I error), usually set at 5%, whether the
trial is one tailed or two tailed; β, the probability of concluding no difference
between the groups when one exists (false-negative rate also known as type II
error); and the desired power (1-β) to find a true difference if one exists between
the treatments. Power is the ability to detect an effect, if, in fact, an effect
actually exists; it is strongly influenced by sample size and projected differences
between treatment groups. Sample sizes are usually projected to yield power of
80% or greater so that the false-negative rate is 20% or less. Small pilot trials are
not considered useful in determining sample size as the confidence intervals are
large (21). A confidence interval, expressed as a percentage of probability such
as 90%, 95%, or 99%, is an interval estimate in which a derived value such as a
mean or median might lie. Thus, a large confidence interval suggests a less
reliable estimate of the statistical parameter in question and may lead to an
underestimation of the necessary sample size. Sample size estimates may utilize
previously published response rates, when available. Suppose an investigator
wanted to propose a trial of bupropion for the treatment of methamphetamine
use disorder. Previous trials had reported end-of-treatment placebo response
rates of 7% (22), 14% (23), and 19% (24). Of note, Elkashef et al. (22) enrolled
both individuals who used methamphetamines less-than-daily and those who
used daily, while the higher placebo response rates reported by Heinzerling et al.
(23) and Anderson et al. (24) were in those who used methamphetamines less-
than-daily. Thus, use characteristics may be taken into account when selecting
appropriate placebo response rates. The sample size can then be estimated using
the placebo response rate and the proposed differential response in the treatment
group. In the absence of literature denoting a drug–placebo difference or placebo
response rates, the investigator must choose a difference thought to be clinically
meaningful. The placebo response rate might be estimated from other clinical
trials involving the substance-using population of interest. Once this is known,
the estimated sample size can be calculated (25). The larger the hypothesized
difference between the two groups, the smaller the sample size estimate for the
trial response rates in clinical trials can be. Trials in substance-using populations
may have a higher dropout rate than trials in other disciplines. For example,
dropout rates were >40% in those who used cocaine in 8-week randomized trials
(26), 47% in a 12-week trial of those who used methamphetamines (27), at 50%
in those who smoked cigarettes in a 13-week pharmacotherapy trial (28), 26%
and 54% for patients receiving methadone or buprenorphine in a 24-week trial
(29). Trials with high dropout rates have missing data issues that can
compromise the integrity of the findings, likely leading to type II errors. One
way to reduce this possibility would be to increase sample sizes to correct for the
high dropout rates.
Another form of missing data in clinical trials is data that is missing
intermittently during a clinical trial. Three types of intermittent missing data
have been characterized (30,31). These are data missing completely at random
(MCAR) defined as being completely unrelated to any constructs being studied,
missing at random (MAR) defined as possibly related to observed values but
completely unrelated to unobserved outcomes, and missing not at random
(MNAR) defined as related to unobserved outcomes. Multiple imputation and
full information maximum likelihood models are valid when used to analyze
used to MCAR and MAR data (32,33), whereas MNAR data should be subjected
to sensitivity analyses (34,35).
Statistical Analysis Plans

Statistical analysis plans should specify the proposed analyses for primary,
secondary, and exploratory outcomes. The statistical analysis plan can be
modified up to the breaking of the blind in a double-blind trial. The plan should
define the intent-to-treat (all randomized participants whether they received the
intervention or not and whether they may or may not have had data
assessments), the modified intent-to-treat (usually randomized, received the
intervention, and had at least one assessment), and the per protocol (usually the
adherent population that completed the protocol with minimal or no missing
data) populations, state the null hypothesis (no difference between groups) and
the alternate hypothesis (there is a difference between groups) for a superiority
trial, anticipate missing data and define how the missing data patterns will be
analyzed, and describe the methods that could be used for missing data in the
determination of efficacy. It should be noted that there is no universal set of
recommendations from regulatory agencies as to how to handle missing data
(ICH E9 Statistical Principles for Clinical Trials). The statistical analysis plan
should describe the monitoring and reporting of adverse events, with particular
emphasis on events of significance, that is, deaths, near-deaths, and other SAEs.
Statistical Significance and Effect Sizes

A statistically significant drug–placebo difference obtained in a superiority trial
(usually p < 0.05) may be due to bias, chance, fraud, or a true effect. Given the
possible causes of the statistically significant results, the significance of p < 0.05
is commonly but incorrectly interpreted to mean that there is a 5% probability
that the null hypothesis is true. Thus, investigators may overestimate the veracity
of the findings. To avoid overstating a statistically significant result, it has been
recommended to report effect sizes in conjunction with p values (36). An effect
size is a measure of the magnitude of an effect. For example, Cohen’s d, defined
as the difference between two means divided by the pooled standard deviation, is
a measure of effect size (37). Cohen’s d effect sizes are defined as small (0.2),
medium (0.5), or large (0.8 or greater).
The reproducibility of the results and the effect size can be tested though
replication studies, one of the foundational principles of the scientific method.
Reproduction of study results by different investigators in a different set of
patients with the disorder adds credence to the findings. In the case of data
needed for drug approvals, the concept of “adequate and well-controlled studies”
was entered into law in 1962 with the passage of the Kefauver-Harris
amendments of the Federal Food, Drug, and Cosmetic Act. Thus, with rare
exceptions that are spelled out in the Food and Drug Modernization Act of 1997,
the FDA requires replication of study results for drug approvals (38). NIH has
also issued a guidance for investigators to enhance rigor and reproducibility of
grant findings (39). Thus, both the FDA and NIH encourage rigor in designs to
enhance the possibility of replication of findings.
THE RESEARCH QUESTION DICTATES

VARIOUS ASPECTS OF TRIAL DESIGN
Superiority Designs
Superiority designs: In randomized, efficacy, and effectiveness trials, the
outcome of interest is whether one intervention comparator produces a superior
outcome versus the comparator. For instance, in a double-blind, placebo-
controlled efficacy trial, the “null hypothesis” is that there are no differences
between the active and placebo medication groups. If statistically significant
differences are found, the null hypothesis is rejected and the alternate hypothesis
(medication efficacy) is accepted. In the comparison of buprenorphine 16 mg,
buprenorphine/naloxone 16/4 mg, and placebo, the proportion of urine samples
negative for opioids in the first month of the trial was 17.8%, 20.7%, and 5.8%,
respectively (p < 0.001 for both active medication groups) (4). Missing urines
were categorized conservatively as “not negative.” The reduction in opioid use at
4 weeks was considered to demonstrate efficacy of the buprenorphine and
buprenorphine/naloxone tablet formulations over placebo.
Another type of superiority design is a comparison of a test medication to an
active control group. Johnson, Jaffe, and Fudala (40) randomized 162 individuals
using heroin to daily doses of 8 mg of sublingual buprenorphine or 20 mg of oral
methadone and 60 mg of oral methadone. A double-blind, double-dummy design
was used to maintain the blind; that is, participants randomized to the
buprenorphine treatment received placebo oral methadone and those randomized
to one of the methadone groups received placebo sublingual buprenorphine. (Of
note, the double-dummy design is employed to mask treatment assignment when
disparate dosage forms are being compared.) Urine samples were collected three
times weekly for the 17-week maintenance phase of the study and analyzed for
the presence of opioids and cocaine. The buprenorphine, methadone 20 mg, and
methadone 60-mg group participants submitted urines that were 53%, 29%, and
44% negative for opioids, respectively. The reductions of opioid use in the
buprenorphine group and 60-mg methadone group were superior to the
percentage noted in the 20-mg methadone group (p < 0.001 buprenorphine vs. 20
mg methadone; p = 0.04 methadone 60 mg vs. methadone 20-mg group). Thus, a
superior response in comparison to a dose of an active control is considered to
demonstrate efficacy. Moreover, assay sensitivity was demonstrated as a higher
dose of methadone was superior to a lower dose of methadone.
Dose–response studies also fall under superiority designs. Since the field of
addiction medicine is mostly dealing with patients with chronic conditions (such
as addiction), several doses of a medication should be tested in a parallel, fixed
dose group design. A statistically significant positive slope is considered to be
evidence of efficacy of a medication (ICH-E4 dose–response information to
support drug registration) although the lowest dose should also have evidence of
efficacy from other studies. Multiple, ascending doses of sublingual
buprenorphine (1, 4, 8, and 16 mg/d) were assessed for their ability to reduce
opioid use in opioid-dependent (DSM-III) patients (41). Although the a priori
comparison for determination of efficacy was the difference in urines negative
for opioids between the 1- and 8-mg dose groups (the 8-mg group had more
urines negative for opioids (p < 0.0001), and a higher percentage of patients with
13 consecutive negative urines (p < 0.0001)), the trial could also have been
analyzed for a dose–response relationship. For example, there was a doubling
and tripling of the percentage of participants in the 8- and 16-mg groups who
achieved 13 consecutive negative urines, respectively, compared to the 1-mg
dose group.
Superiority trials may sometimes add a third arm, an active control group. If
the active control demonstrates efficacy versus the placebo group, the trial is said
to demonstrate “assay sensitivity” as it aids in the interpretation of findings seen
with the drug in question. For example, varenicline was tested against bupropion
and placebo for efficacy in smoking cessation. Bupropion was more effective
than placebo, demonstrating assay sensitivity. Varenicline’s efficacy was
superior to both bupropion and the placebo groups in this study (42). Conversely,
if the active control fails to demonstrate efficacy versus placebo, it can be
considered to be a “failed trial” rather than a failure to show efficacy if the effect
seen with the drug in question also does not separate from placebo responses.
Dose–response relationships can also be studied in behavioral therapy trials.
Some CM trials evaluate the “dose” or magnitude of a reinforcer given in
response to adherence with the targeted behavior. Petry et al. (43) evaluated two
different magnitudes of monetary reinforcement ($250 or $560) in 106
individuals using cocaine. Both groups reduced their cocaine use relative to
standard care. The higher magnitude monetary reinforcement group also had the
longest duration of abstinence relative to standard care (p < 0.05).
The frequency of counseling given in medication-assisted treatment is
another example of assessment of “dose–response” relationships. One hundred
sixty-six DSM-IV–defined opioid-dependent participants were randomized to
standard medical management (SMM) and either once weekly (group 1) or three
times weekly medication dispensing (group 2) or enhanced medical management
and three times weekly medication dispensing (group 3; Fiellin et al. (44)). The
percent negative urine samples for opioids in groups 1, 2, and 3 were 44%, 40%,
and 40%, respectively, p = 0.82. Enhanced medical management and three times
per week dispensing did not increase the treatment response.
Noninferiority Designs
Noninferiority designs: A clinical trial that compares two active treatments with
the purpose of determining whether the efficacy or effectiveness of one
treatment is not worse than the standard established behavioral or
pharmacological therapy is a noninferiority trial. Noninferiority trials, previously
called equivalence trials, must be of high quality and rigorously conducted. A
poorly conducted noninferiority trial could yield a result consistent with
noninferiority when a difference between the two treatments could actually exist.
Design considerations include the following: (a) what is the noninferiority
margin?; (b) what is the sample size and power to detect differences between the
treatments?; (c) how will the blind be maintained?; (d) will the study population
be similar to those in which the standard treatment was already established?; (e)
is the population being analyzed the “intent-to-treat” population, a modified
“intent-to-treat” population, or a “per protocol” population that was fully
compliant with the protocol?; in an ITT population, none of the patients are
excluded and the patients are analyzed according to the randomization scheme.
In other words, for the purposes of ITT analysis, everyone who is randomized in
the trial is considered to be part of the trial regardless of whether he or she is
dosed or completes the trial; (f) what statistical analyses are being used?; and (g)
will sensitivity analyses be conducted to test the robustness of the results?
The noninferiority margin can be determined by the treatment effect noted in
drug versus placebo superiority trials. Absent such data, the noninferiority
margin can be established by expert consensus as it was in the case described
below. Noninferiority margins can be as high as 50%, but smaller margins in the
20% range certainly meet the FDA guidelines for a noninferiority margin choice
(45). If a 20% margin is chosen, noninferiority of the new treatment may be
concluded if the lower bound of the 95% confidence interval (CI) of the
difference between the treatments is within the lower bound of the 95% CI of the
intent-to-treat population, that is, all randomized participants. The sample size
needs to be justified in the protocol and the power should approach or be >90%.
It should be appreciated that small sample sizes would bias toward a failure to
find differences between the treatments due to a lack of power.
A recent noninferiority trial of buprenorphine implants versus sublingual
buprenorphine is an example of a noninferiority trial in a substance-using
population (46). The purpose of the study was to determine whether
buprenorphine implants were capable of maintaining low opioid use or
abstinence compared to daily sublingual buprenorphine therapy in currently
stable, DSM-IV–defined opioid-dependent patients currently on a sublingual
buprenorphine/naloxone dose of 8/2 mg or less. Stability was defined as being
on a stable dose of buprenorphine/naloxone with abstinence from illicit opioid
use for at least 90 days. To maintain the blind, participants were randomized in a
1:1 ratio to buprenorphine implants with placebo sublingual
buprenorphine/naloxone tablets or sublingual buprenorphine/naloxone tablets
with placebo implants. Further, since the buprenorphine implants were
distinguishable from the placebo implants, the study employed two sets of
physicians at each of the 21 sites: one group implanted study participants and the
other group treated the participants during the 6-month study. Participants were
assessed at week 1 and thereafter at 4-week intervals. A total of 10 urine samples
were collected, at monthly visits and four times at random during the 6 months
of treatment. A treatment responder was defined as a participant who had 4 out
of 6 months in which no illicit opioid use was detected, either by urine testing or
self-report. Urine was analyzed for multiple opioids (codeine, fentanyl,
hydrocodone, hydromorphone, methadone, morphine, oxycodone, and
oxymorphone) by liquid chromatography–tandem mass spectrometry. A 20%
penalty was imputed to missing urines in the buprenorphine implant group,
adding to the rigor of the trial. Participants could receive supplemental
buprenorphine, if necessary. Drug craving, withdrawal, and adverse events were
also measured.
Power was estimated to be 87.3%, assuming each group had 75%
responders. One hundred seventy-seven patients were admitted to the trial. The
trial employed a modified intent-to-treat analysis, defined as those randomized
to treatment, received implants and sublingual doses of buprenorphine/naloxone
or placebo, and had at least one post-baseline assessment.
One hundred sixty-five participants completed the study. The buprenorphine
implant and the sublingual buprenorphine groups have 96.4% and 87.6%
responders, respectively. The lower bound of the 95% CI was within the lower
bound of the study confidence interval, establishing noninferiority. Once
noninferiority is established, the group difference can be tested for superiority.
The response in the buprenorphine implant group was not only noninferior; it
was superior to the response rate in the sublingual group (p = 0.03). Sensitivity
analyses were conducted; the cumulative 6-month abstinence rate in the
buprenorphine implant group (85.7%) was superior to the abstinence rate in the
sublingual buprenorphine/naloxone group (71.9%) (p = 0.03).
Adaptive Designs
Clinical trials in which sequential assignments of participants to new treatments
are made following predetermined decisions rules are called adaptive designs
(47). These designs can more closely replicate the type of care clinicians often
provide to patients by allowing those patients to receive sequential treatments
contingent upon their clinical response. Adaptive designs take into account the
order of treatments and adherence to treatment and response of participants
during the trial (48–50). The Sequential Multiple Assignment Randomized trial
(SMART) design has been proposed to address the types of issues facing
clinicians in treating patients with SUDs in which multiple treatments, both
behavioral and pharmacological, are available. In the simplest model,
participants are randomized to a treatment group and are assessed for
response/nonresponse at a decision point. Those patients who do not respond can
then be assigned an alternate treatment assignment while responders may
continue with their treatment. Study participants can also be randomized twice,
initially to a treatment group and then following a decision point, to a second
randomized assignment. Advantages of the SMART design are that it provides
options for nonresponding study participants and it allows an assessment of the
potential synergistic effects of a treatment sequence. An example of a SMART
design in the substance use field is the treatment of DSM-IV–defined heroin
dependence with either optimal methadone treatment or stepped care with
buprenorphine (51). The purpose of the study was to determine whether
buprenorphine could be started as a first-line therapy with switching to
methadone if buprenorphine treatment was less than satisfactory. In this study,
heroin-dependent participants were randomized 1:1 to initial maintenance doses
of 70 mg methadone or 16/4 mg of buprenorphine/naloxone. Transitions were
considered at 2-week intervals. Methadone-assigned participants could receive
dose increments of 10 mg up to a 120 mg/d maximum based on the following
criteria: missed visits within the transition period, insufficient blockade,
withdrawal symptoms, or urines positive for illicit opioids. The
buprenorphine/naloxone-treated group could receive 8 mg increases during
transition periods up to 32 mg using the same criteria. The buprenorphine group
could transition to methadone if the 32-mg dose was considered insufficient. In
the methadone group, 38 of 48 participants (79%) completed the study. In the
buprenorphine group, 77% completed with 17 participants completing on
buprenorphine (mean dose = 29.6 mg/d), 20 switched to methadone (mean dose
= 111 mg/d), and 11 dropped out. The proportion of negative urines increased
over time in both groups with no statistical difference between the groups (p =
0.87). Retention was essentially equivalent across treatment arms; the
buprenorphine arm was noninferior to the methadone group (odds ratio = 1.02,
95% CI, 0.65–1.60). The authors concluded that a significant proportion of
patients could be treated with buprenorphine/naloxone therapy in a stepped care
model with switching to methadone when needed.
OUTCOME METRICS USED IN

CLINICAL TRIALS
Abstinence and/or reduction of drug or alcohol use are often primary outcome
variables in clinical trials involving substance-using populations. The FDA has a
guidance on the development of medications for the treatment of alcohol use
disorder that illustrates the FDA’s current thinking on outcome measures and
trial designs (52). The FDA advises that trials of treatments for alcohol use
disorder should employ randomized, placebo-controlled, superiority designs of
at least 6 months duration with a primary end point based on a responder
analysis. A responder is either a participant who is abstinent for a significant
period of time at the end of a trial, following a negotiated grace period, or a
participant who has not experienced any heavy drinking days (defined as having
more than four standard drinks for men or three standard drinks for women per
drinking occasion). The requirement for the 6-month trial duration is based on
literature that abstinence at 6 months predicts abstinence at 5 years (53), with
health benefits accruing to the abstinent individual. The FDA’s acceptance of the
validity of the percent heavy drinking days end point as a surrogate for clinical
benefit is based on studies examining alcohol consumption using a graduated
frequencies measure from the National Alcohol Surveys (54), the National
Epidemiological Survey on Alcohol and Related Conditions (55), an analysis of
transitioning in and out of problem drinking in a 7-year longitudinal study (56),
and a pooled analysis of three clinical trials involving problem drinkers (57).
Although an unofficial opinion, an FDA medical reviewer has opined that
efficacy trials of medications for treatment of stimulant use should have similar
durations and outcome measures (58). The responder definition in these trials
would include those participants exhibiting abstinence of a duration that predicts
“ongoing abstinence and/or good psychosocial functioning and physical
functioning” and those with less than full abstinence if the remaining level of use
“can be considered nonharmful.” This is in contrast to the recommendations of a
group of research and treatment experts who opined that a 50% reduction in drug
use was clinically meaningful (59). An analysis of several continuous variables
of cocaine use (percent days abstinent, percent negative urine samples,
maximum days of cocaine abstinence) and one dichotomous variable (at least 3
weeks of abstinence), measured in multiple clinical trials, related these
improvements to reduced cocaine use and improvement of functioning on the
addiction severity index (ASI) (60) during a 12-month follow-up period (61).
Cocaine abstinence and reduced use of cocaine were also been shown to
correlate with decreased levels of endothelin-1 (ET-1), a marker of endothelial
dysfunction (62). Moreover, the number of cocaine use days was correlated to
the reduction in ET-1 levels.
Quantification of Substance Use

The measurement of drug or alcohol use can be by biological assay, self-report,
or a combination of the two measures (63). Urine is the most tested biological
fluid tested for the presence of drugs, likely due in part to the noninvasive nature
of collecting urine. Relating the measurement of drugs or alcohol in urine to use
is more complex than originally thought. Detection times for drugs and alcohol
are reported in Table 6-1. Alcohol and most drugs, with the exception of
cannabis and PCP, have detection times in urine of 2-4 days. Thus, urine
sampling once a week would not cover the potential days of use, possibly
resulting in falsely concluding that a patient was abstinent. Increasing urine
sampling to 3 days per week certainly covers the majority of the week but brings
up the problem of frequent research visits and carryover, that is, consecutive
semiquantitative urine positive samples in the absence of new use. Quantitative
analysis of benzoylecgonine has been proposed as a method to correct carryover
in assessment of cocaine (71). Urine samples and self-report can be discrepant
for identification of use. An algorithm integrating both quantitative urinalysis of
benzoylecgonine and self-report of cocaine use has been developed (63). Finally,
clinical trials in substance-using populations involve missing data, and urinalysis
data are no exception. Missing urines can be imputed as positive, neutral, or
negative, leading to different results in terms of percent days abstinent or
consecutive days abstinent. The worst-case scenario can produce biased
estimates in a treatment effect. Missing data in the COMBINE study were
subjected to five imputation methods: complete case analysis, last observation
carried forward, missing = heavy drinking, multiple imputation (MI) method,
and full information maximum likelihood (FIML). The MI and FIML produced
the least biased estimates of the effect of naltrexone (72).
TABLE 6-1 Detection Times for Drugs and Alcohol in

Urine Samples
Measuring Withdrawal Syndromes
Withdrawal syndromes associated with discontinuation of alcohol, caffeine,
cannabis, opioid, sedative–hypnotics, stimulants, and nicotine/tobacco are
described in DSM-5 (73). Management of withdrawal symptoms is recognized
by the FDA as a potential indication for use of medications in alcohol and opioid
withdrawal. Management of nicotine/tobacco withdrawal is considered to be a
mechanism affecting efficacy of nicotine replacement therapies (74). Although
management of withdrawal could be a separate indication for some conditions,
viz., cannabis, sedative–hypnotic, and tobacco/nicotine withdrawal if clinical
benefit could be demonstrated, for the most part, it is relegated to being a
secondary outcome measure in clinical trials. There are multiple withdrawal
scales to measure components of opioid withdrawal: the Short Opiate
Withdrawal Scale (75), the Subjective Opiate Withdrawal Scale and the
Objective Opiate Withdrawal Scale (76), and the Clinical Opiate Withdrawal
Scale (77). Alcohol withdrawal domains can be reliably measured using the
Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) (78,79).
Measuring Drug Craving

Drug craving: There is no universal definition of craving. It is usually defined as
a conscious awareness of a desire to use a drug (80). Craving is included in the
DSM-5 diagnostic criteria to consider for a SUD and in the ASAM definition of
addiction. In the ASAM definition of addiction, craving is noted as a component
of addiction whereby the individual has increased hunger for drugs or rewarding
experiences. Craving has a complex relationship with drug use. A full discussion
of craving and the limitations of its measurement are beyond the scope of this
chapter. Craving can be measured as a single-item construct, but this has been
criticized as lacking the breadth to describe dimensional aspects of the
experience (81). Craving can also be measured as a multi-item construct like the
questionnaire on smoking urges (81). In clinical trials, craving is usually
measured as a secondary outcome variable that often serves a role in the
convergent validity of behavioral findings, that is, reduced craving associated
with reduced use or abstinence. Craving can be measured in real time using
ecological momentary assessment techniques where study participants are
queried on craving and its relationship to drug intake or abstinence through
mobile devices (82).
Measuring Cognitive Function

Cognitive function: Although not routinely measured in clinical trials, cognitive
functioning may impact outcomes in trials and treatment. Individuals with
cognitive deficits have higher dropout rates in substance use treatment (83,84),
and substance-using populations often have deficits in cognitive tests. For a full
discussion of cognitive deficits in substance-using populations and their possible
remediation, the reader is referred to Vocci (85). A few examples will suffice.
Those who use cocaine demonstrated cognitive inflexibility (perseverative
responding) in the Wisconsin Card Sorting Test (86, 87). There is some evidence
that medications may be able to affect set-shifting, improving cognitive
flexibility. A 200-mg dose of modafinil corrected a set-shifting deficit in patients
with schizophrenia (88), suggesting that medications can affect perseverative
responding. Attentional bias toward drugs may factor into treatment response.
Poor performance on a drug-related Stroop test (89) and a conventional Stroop
test by cocaine-using patients (90) predicted treatment dropout, although further
research is needed to establish causality. A cognitive battery could be used
during the screening process to evaluate cognitive deficits and balance groups
with respect to cognitive dysfunction. Cognitive tests incorporated into clinical
trials would need to show that improvement was not due to practice effects.
Additionally, improvements in cognition would need to be accompanied by a
clinical benefit to serve as an outcome measure for FDA approval of a
medication.
Psychiatric Scales
There are multiple psychiatric scales used in clinical trials. The Structured
Clinical Interview for DSM-5 (SCID-5) is used to systematically evaluate
psychiatric diagnoses during screening. The SCID-5 has multiple versions,
including a research version and a clinical trial version (SCID-5-CT) that can be
customized to map onto the inclusion and exclusion criteria of a trial. Other
psychiatric rating scales that measure mood disorders used in trials involving
substance-using populations are the Beck Depression Inventory (91), the
Hamilton Depression Rating Scale (92), and the Hamilton Anxiety Rating Scale
(93). These scales can be incorporated into screening procedures as ancillary
inclusion or exclusion criteria, as stratification criteria, or as outcome measures
(94). A wide array of psychiatric scales have been developed for various clinical
trials over the decades. For example, scales used in the DSM-5 field studies can
be found at www.psychiatry.org/dsm5. A Handbook of Psychiatric Measures has
also been published (95).
Addiction-Focused Scales
The ASI measures problems associated with addiction in several domains: drug
and alcohol use, medical and psychiatric issues, legal problems, family issues,
and employment status (60,96). Although originally designed to tailor treatment
to address problems of patients entering treatment, it has been used in clinical
trials to measure alcohol and drug use and associated functioning (97). A fairly
comprehensive and easily accessible resource for instruments used in NIDA
studies can be found at https://datashare.nida.nih.gov/assessments. Reduction of
HIV Risk ScalesReduction of HIV Risk Scales The Risk Assessment Battery
measures behaviors associated with drug use and sexual behavior that are
associated with HIV risk. It is one of the scales used in trials with substance-
using populations that measure infectious disease risk. A computerized version
exists (98). Drug and sexual risk subscores can be evaluated separately. It is
usually measured at the beginning and at the end of a trial. The HIV Risk
Behavior Scale is an 11-item questionnaire that is also used to quantify drug and
sexual risk behaviors that may put the individual at risk of contracting or
transmitting HIV (99).
Quality of Life Measures

The Medical Outcome Study (MOS) 36-item short form health survey (SF-36)
assesses eight domains of physical and emotional health (100). It can be used to
assess changes in health across time in a clinical trial and could be used to
satisfy the FDA’s request to demonstrate that changes in drug use produce
medical benefit or improvements in well-being to an individual. Another quality
of life scale that has gained wide usage is the EQ-5D (101). This scale measures
the domains of mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression. It has been translated into more than 60 languages, making it
a good choice for measuring quality of life issues in international clinical trials
where multiple languages would be used in data collection.
Patient-Reported Outcome Measures

The NIH has developed a standardized, validated Patient-Reported Outcome
Measures Information System (PROMIS) to fill a gap in research on self-
reported health measures (https://commonfund.nih.gov/promis/index).
Approximately 70 domains of self-reported health can be evaluated using
PROMIS. It has been translated into multiple languages and is available on
paper, electronic, mobile, and Web-based platforms.
Pharmacokinetic Measures
The plasma pharmacokinetics of a medication can yield important information
on dosing intervals and pharmacokinetic–pharmacodynamic correlations. For
example, daily dosing of 8 mg sublingual and alternate daily dosing of 16 mg
sublingual buprenorphine yielded trough plasma levels of 0.80 ng/mL and 0.77
ng/mL, respectively (102). There were no differences in withdrawal scores,
suggesting plasma concentrations above 0.7 ng/mL would suppress withdrawal
symptoms. Higher doses of buprenorphine yielding higher plasma concentration
and higher mu receptor occupancy were associated with greater blockade of
hydromorphone’s effects (103). Blockade of hydromorphone agonist effects
required buprenorphine plasma concentrations ≥3 ng/mL (104).
In vaccine trials, the antibody titer may be correlated to efficacy. Vaccines
will produce a variable immune response, resulting in an array of antibody titers.
In a cocaine vaccine trial, 21 participants with IgG levels ≥42 μg/mL had more
cocaine-negative urines than placebo-dosed participants (p < 0.03) (105). The
correlation to antibody titers can guide future vaccine development.
Healthcare Service Utilization Measures

Healthcare service utilization can be measured from the standpoint of the patient
or the provider/healthcare system (106). Indicators of healthcare quality include
accessibility to treatment, continuity of treatment, the range of services offered,
and the integration of care (107). These indicators appear to be more geared to
evaluating an existing treatment system but could be incorporated into a clinical
trial evaluating one or more of these indicators. For example, treatment
accessibility has been studied in a trial where patients seeking methadone
maintenance treatment were randomized to an interim methadone group that
received methadone for up to 120 days or to a waiting list control (108). To
evaluate continuity of treatment and range of services, the Treatment Services
Review (TSR) surveys treatment services addressing the seven domains of the
ASI provided to patients receiving alcohol or substance use counseling
(109,110). Again, it is geared more toward addressing issues in the extant
treatment system, but it could be used to evaluate the amount of services
accessed by participants during a clinical trial.
Cost Analysis–Related Measures

Although rarely a primary outcome measure, economic data obtained during
effectiveness trials can assess the economic value of an intervention (111). An
economist should be involved in the design of the trial if an economic analysis is
contemplated. The main types of analyses are cost-effectiveness analysis
measuring benefits in terms of quantity or quality of life as a unitary construct,
cost–utility analysis measuring quantity and quality of life across several aspects
of health and well-being (eg, quality-adjusted life years or healthy years
equivalent are estimates of the benefit of a healthcare intervention), and cost–
benefit analysis addresses whether the benefits associated with an intervention
exceed its costs. For example, a cost and cost-effectiveness analysis of the nine
treatment groups comprising the COMBINE study was conducted in terms
percent days abstinent, the incremental cost per patient to avoid heavy drinking,
and the incremental cost per patient of achieving a good clinical outcome (112).
Three intervention groups were noted to be cost-effective relative to the other
treatment groups: medical management (MM) with placebo, MM with
naltrexone, and MM with naltrexone and acamprosate. A benefit–cost analysis
comparison of interim versus standard methadone treatment failed to reveal any
significant monetary differences between the interventions although there was a
net monetary benefit noted in the combined study sample (113).
Treatment Adherence Measures
Adherence to therapy is an important variable to measure in both behavioral and
medication trials. Behavioral therapy sessions can be recorded and assessed for
fidelity to the therapy and the therapist’s competence in delivering the therapy
(114). Adherence to medication regimens is an issue in clinical trials for all
pharmacotherapy trials except those in which the administration of the
therapeutic agent is directly observed. Medication adherence can be measured
through multiple means: addition of riboflavin into oral medications for
measurement in urine samples (115), pill count and medication diaries (116),
medication event monitoring systems (MEMS) in which opening of a bottle
containing medication is captured electronically (117), self-report (118), direct
measurement of the medication in urine (23,24), capsule photographs taken with
cellular telephones (119), and pharmacy fill–refill. The reliability and
comparability of the various forms of adherence are another consideration in
designing clinical trials. In a study in people who used cannabis, riboflavin
(vitamin B2) and serum 6-OH buspirone levels showed a declining adherence to
medication, whereas pill counts and diaries overreported adherence (116),
calling into question the reliability of self-report.
The effect of medication adherence can be illustrated in clinical studies
attempting to replicate the initial finding of the efficacy of bupropion to reduce
methamphetamine use (22). A NIDA-funded replication study of bupropion in
individuals who used methamphetamines less than daily methamphetamine
reported no difference in reduction of methamphetamine use at the end of the
trial between the bupropion and placebo groups (p = 0.32) (24). Adherence,
measured by urinary bupropion levels, was reported in 47% of the bupropion-
treated group. Thus, this could be considered a failed trial rather than a failure to
replicate. A second trial of bupropion in individuals who used
methamphetamines less than daily found no significant difference in abstinence
between the bupropion (29%) versus placebo (14%) groups in the intent-to-treat
analysis (p = 0.08) (23). Medication adherence, measured by bupropion plasma
levels, was low (32%). A post hoc analysis of medication-adherent (13/41)
versus nonadherent bupropion participants (28/41) reported end-of-treatment
abstinence in 54% and 18%, respectively (p = 0.018). These positive and
negative findings show the impact of adherence in the replication of bupropion’s
efficacy.
MONITORING AND QUALITY
CONTROL
Data gathered in clinical trials are entered into a confidential database during the
trial. The Public Health Service Act (301 (d), 42 U.S.C. 241 (d)) authorizes
investigators performing trials involving substance-using populations to
withhold information from civil, criminal, administrative, or legislative bodies
unless the information is considered a reportable issues, that is, child abuse,
elder abuse, or threats of violence toward others (120). The privacy of research
participants is ensured by the obtaining a Certificate of Confidentiality from the
NIH or the FDA. Participants’ data are coded to establish confidentiality.
Confidentiality at the research site is maintained by keeping the linking file
separate from the database, password protecting the database, and restricting
access to individuals who need to input or review data. The informed consent
document explains that certain outside entities may review case report forms and
the database, that is, the FDA, industry monitors if the trial is industry
sponsored, or NIH personnel if the trial is NIH funded. Industry-sponsored trial
monitors visit a clinical site at least three times: before participants are enrolled,
during the study, and at the end of the study. The privacy of the research
participant is maintained since only coded data are reviewed.
Safety is monitored at the clinical site by the investigators and by the IRB,
the DSMBs, the FDA, the pharmaceutical industry (if industry sponsored), and
the NIH (if the study is NIH funded). The protocol contains the definition of
serious adverse events (SAEs) and how, when, and to whom SAEs will be
reported. The investigators have the primary role for participant safety and can
discontinue a participant if they think it is in the participant’s best interest to do
so. The IRB reviews the protocol prior to study commencement and then
periodically reviews enrollment and adverse events. Sometimes, a medical
monitor (who is usually blinded with respect to treatment assignment) will
review safety issues and advise investigators. In other cases, a DSMB, a
collection of clinical trial experts and medical experts that advise the
investigators on trial design features, study enrollment, and safety and efficacy
issues, will be chartered. The DSMB, when appropriate, can recommend
changes in the protocol, up to and including termination of the study. It is the
investigator’s responsibility to report DSMB recommendations to the IRB and
other regulatory entities. The NIH requires DSMBs for multicenter trials funded
by NIH (121) and encourages consideration of setting up a DSMB for trials
involving randomized, blinded data (1).
The public reporting and monitoring of national and international clinical
trials are done through the ClinicalTrials.gov website. Section 801 of the FDA’s
Amendment Act mandates that applicable clinical trials, including NIH-funded
trials, be reported on ClinicalTrials.gov. Although phase I studies are exempt
from posting on the site, many phase I studies are posted.
REPORTING RESULTS IN A JOURNAL

ARTICLE
There are over 65 journals in the addiction medicine field. An important
consideration by investigators is what journal to send their results to. There is a
website specifically designed to assist investigators with this decision process
(www.parint.org). This website offers guidance and a tutorial on the process of
journal selection and manuscript preparation. Once a journal has been selected,
the authors should visit that journal’s website to determine the formatting, word
count, and other specific requirements, for example, reporting
oversight/institutional review and informed consent procedures. The CONSORT
website offers an information checklist of issues to consider when reporting
randomized trial results (www.consortstatement.org). The outcome measures and
statistical methods used in a trial should be described in the methods section of
the paper. The statistical methods used for imputation of missing data should be
stated. Planned versus post hoc analyses should be clearly described as the
former carries more weight with reviewers, editors, and the journal readership. It
is recommended that effect sizes accompany the p values so that readers can
judge the strength of the effects reported. The conclusions and recommendations
to changes in practice should not go beyond what is supported by the results.
CONCLUSIONS
Clinical trials in substance-using populations must comply with all the
requirements of performing investigations in human subjects. Additionally, there
are unique challenges to performing and interpreting clinical trials in substance-
using populations. The determination of abstinence is not straightforward as
carryover may be observed in urine samples, necessitating a correction
algorithm. Moreover, there is no consensus as to what constitutes an adequate
duration of abstinence or what level of improvement in psychosocial functioning
or well-being would be acceptable in those who do not achieve full abstinence.
More research is needed to engage the FDA in determining the issue of what
constitutes an adequate response to a pharmacotherapy for cannabis, opioid, and
stimulant disorders. The NIAAA has worked with the FDA in determining the
level of drinking reduction that is associated with a therapeutic response to a
pharmacotherapy (52). Additionally, high dropout rates and other missing data in
clinical trials in substance-using populations may lead to type II errors and
require sophisticated analyses to account for the missing data. Adherence to
taking medication, although not unique to patients with SUDs, is low to
moderate in this patient population, another variable that could lead to a type II
error. Clinical trial designs need to consider these issues in the design and
analysis of future trials in patients with SUDs with the goals of preventing
missing data, improving medication adherence, and increasing the
reproducibility of results.
Acronyms Explained
Certificate of Confidentiality (CoC)
A Certificate of Confidentiality is a document obtained from either the NIH or
the FDA that allows a researcher to refuse to disclose names or other identifying
information about participants in a clinical trial in response to local, state, or
federal subpoenas.
Data and Safety Monitoring Board (DSMB)

A DSMB is composed of medical and clinical trial experts who are charged with
making recommendations regarding study design, enrollment, efficacy issues up
to and including trial termination due to overwhelming efficacy, and protocol
changes due to safety issues up to and including trial termination for safety
reasons. DSMB functions and oversight are distinct from the requirement of
study review and approval by an institutional review board. A DSMB is required
for all NIH-funded multicenter trials and is encouraged in other situations.
Institutional Review Board (IRB)

An institutional review board is composed of a group of at least five individuals
possessing professional competence to review research activities and able to
ascertain the acceptability of proposed research in terms of institutional
commitments and regulations, applicable laws, and standards of professional
conduct and practice.
Investigational New Drug (IND) Application

A commercial IND is an exemption to the law that a pharmaceutical company
must have an approved drug in order to ship across state lines. The
investigational drug can then be shipped to investigators across the United States
and internationally if the FDA approves the IND. Another type of IND is an
investigator IND, obtained by clinical investigators to study already marketed
drugs for indications other than those approved in the labeling.
New Drug Application (NDA)

An NDA is a compilation of relevant information regarding the chemistry,
manufacturing control data, pharmacology, pharmacokinetics, toxicology, and
clinical and statistical analyses of data on a drug product that a pharmaceutical
company submits to the FDA in pursuit of marketing approval.
Clinical Trial Phases

Phase I studies are the initial studies of a drug in human subjects. Most phase I
drug research is conducted in healthy volunteers in inpatient settings. The usual
number of participants is 20-80 and the emphasis is on safety and
pharmacokinetics of the drug. In the development of medications for substance
use disorders, the FDA often requests an interaction study of a putative
medication with a known drug of abuse, for example, cocaine, in cocaine-
experienced nontreatment seeking volunteers before allowing outpatient studies
to commence in persons with cocaine use disorder.
Phase II studies, usually conducted in 100-200 study participants, are the
initial determination of a drug’s efficacy and safety in the intended patient
population.
Phase III studies are intended to replicate the efficacy of a drug in an
expanded population and to explore the efficacy and safety of the proposed
dose range, fixed versus flexible dosing strategies, duration of therapy, and
interactions with concomitant medications. It is not uncommon to have 1000-
3000 study participants in phase III studies in order to capture serious adverse
events that occur at low incidence rates.
Phase IV studies, also known as postmarketing studies, are often
performed to gather further safety data on specific clinical issues, for example,
concerns about hepatotoxicity, under “real-world” conditions. Comparative
effectiveness trials, also conducted in phase IV, compare different treatments
using flexible protocols that allow clinician judgment with regard to dose
changes, for example. The comparison group is often a “treatment-as-usual”
group.
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[HHS website]. February 25, 2003. http://www.hhs.gov/ohrp/regulations-and-
policy/guidance/certificates-of confidentiality/. Accessed November 8, 2016.
121. NIH Policy for Data and Safety Monitoring. [NIH website]. June 10, 1998.
https://grants.nih.gov/grants/guide/notice-files/not98-084.html. Accessed November 8, 2016.
CHAPTER 7
The Addiction Medicine Physician as a
Change Agent for Prevention and Public
Health
Kevin Kunz
CHAPTER OUTLINE
We Are Responsible
Protecting and Promoting The Public Health
The Role of the Addiction Medicine Physician
Transformational Change
A Proven Approach to Effecting Change in Health Care
Summary
WE ARE RESPONSIBLE
There is an urgent need to translate addiction science into everyday clinical
practice, while also translating it into institutional and public policies that
constructively impact health. This text presents a vast array of effective
evidence-based interventions, which can be applied in clinical and community
settings. However, these lifesaving and life-enhancing practices are neither fully
appreciated nor adequately applied. Unhealthy substance use is one of the
world’s largest and most costly health issues. Unhealthy substance use is
prevalent on every continent and in virtually every culture, accounting for the
top causes of preventable death and disability on a global scale. In the United
States, unhealthy substance use and addiction cause 23% of all deaths (1). In the
United States, the unrelenting and accelerating opioid use and overdose crisis of
the last two decades has now brought the attention of medicine and health care to
a sharper focus on all unhealthy substance use.
Despite the availability of a large and growing body of science to guide
effective care, American medicine is primarily focused on treating the
complications of substance use rather than on the prevention and treatment of
substance use disorders (SUDs).
It is the ethical responsibility of every physician to provide competent
medical care and to incorporate current scientific knowledge into his or her
medical practice. Yet SUD have historically been the unattended orphan of the
medical profession. A growing workforce of addiction medicine physicians is
now positioned to join those of addiction psychiatry to drive system-level
changes to improve the quality of patient care and advance population health.
They can do this by serving as expert clinicians, teachers and faculty, and
community or governmental-level change agents. Addiction medicine itself has
entered a new era. The recent recognition of the subspecialty of addiction
medicine by the American Board of Medical Specialties (ABMS) and the
Accreditation Council for Graduate Medical Education (ACGME) has brought
SUD into mainstream American medicine and has increased the opportunity for
all physicians to more effectively address these disorders. There are also ongoing
expansions of governmental and health system initiatives to create and fund
substance use disorder prevention, treatment, and recovery programs. Thus,
medicine and health care at-large are entering the preparation and action phases
for addressing this long neglected global malady. The goal of this chapter is to
offer an introduction to the role of addiction medicine physician leadership in
integrating science and evidence-based practice into systems of care and public
health initiatives, large and small.
PROTECTING AND PROMOTING THE

PUBLIC HEALTH
American medicine and health care may reasonably take pride in the technical
application of science and discovery, yet we rank near the bottom on a global
rating of health—36 of 37 among developed nations (2). This is nowhere more
obvious than in disease and social dysfunction caused or exacerbated by
unhealthy substance use. Unhealthy substance use and addiction is America’s
number one health problem (3,4). Though death is a crude measure of health, it
is informative that nearly a quarter of annual deaths in the United States are
attributable to harmful substance use and addiction (1,5–8). These deaths are
almost always preceded by medical, social, public health, and economic
sequelae of substance use. The good news is that SUD are not only treatable
conditions (9,10) but they are also responsive to well-coordinated prevention and
public health initiatives, which can be informed by leaders in our field. This is
true also for other conditions often referred to as “process” or “behavioral”
addictions, such as gambling disorder, sexual “addiction,” problematic Internet
use, etc.
The current US epidemic of opioid use disorders (11), in which physicians
and medicine are complicit, has propelled attention to the role of individual
physicians, as well as medicine and healthcare systems generally, in the field of
addiction medicine. Physicians and the American public have been sensitized by
the opioid crisis rocking our national health and our collective consciousness.
Concern and calls to action to combat the opioid crisis stand in stark contrast to
the passivity expressed in relation to the high prevalence of nicotine addiction
over the past 50 years and in relation to decades of unhealthy use of other
substances.
Missing from the current approach of medicine today is the front end of the
continuum of healthcare practice: attention to issues of public health and illness
prevention. In this space, every physician and especially every addiction
medicine physician can incorporate new competencies into their professional
practice. Prevention is a woefully neglected aspect of routine medical care when
it comes to substance use: unhealthy substance use is a preventable condition
and addiction is a preventable disease, which when unaddressed become chronic
and more difficult and costly to treat.
Progress in the prevention effort in medicine generally and for substance use
specifically has been restricted in part by our national healthcare systems, which
developed from and are sustained by an acute care disease model (12). There is
sparse implementation of available evidence-based prevention and treatment
strategies, while there are easily accessible advanced and costly treatment
options for late-stage complications of addiction: trauma, organ damage, cancer,
metabolic disorders, psychiatric complications, etc. As well, late-stage
“interventions” for social sequelae of substance use, such as incarceration,
disability, and unemployment assistance, are usually more readily available than
less costly and more effective prevention and public health initiatives. This
entire situation is now being considered “upside down.”
The acute care focus of American medicine has historically rewarded the
short-term care of back-end medical complications of substance use, while
providing minimal reward for front-end and often more cost-effective
prevention. Feinberg (13) suggests that there are other reasons why it is difficult
to gain broad institutional support for prevention: success is invisible, lack of
drama makes prevention less interesting, statistical lives have little emotional
effect, there is usually a long delay before rewards appear, benefits often do not
accrue to the payer for prevention, persistent behavioral change may be required,
bias against errors of commission may deter action, avoidable harm is accepted
as normal, there is a double financial standard in the evaluation of prevention as
compared to treatment, commercial interests may conflict with disease
prevention, advice is inconsistent or changes, and advice may conflict with
personal or religious or cultural beliefs.
In a physician’s interaction with a patient, he or she is expected to engage
and apply specific core competencies learned in medical school, residency, and
community practice. As physicians, this is what we do. It is our passion. Yet for
all the years and money spent on medical education and training, and spent
annually in medical practices and healthcare systems, the profession of medicine
in America has not adopted or implemented adequate competencies and
strategies to systematically improve the population health of our nation’s
citizens.
All physicians must endeavor to weave into their practice a “red thread” of
public health, disease prevention, and governmental policy advocacy, striving to
prevent illnesses from occurring or recurring through educating patients and the
public, providing effective prevention and early intervention services, and when
possible recommending effective public policies and conducting research. Public
health services also include efforts to limit health disparities and promote
healthcare equity, quality, and accessibility (14). A public health approach and
particularly a focus on prevention are essential to effectively address the health
issue of unhealthy substance use, as well as preventing its costly medical and
social consequences.
To address these and other concerns, the landscape of health care in this
country must change. Thibault (15) has noted that this requires addressing the
full continuum of care from prevention and early intervention to chronic disease
management, breaking down the silos of health professional education and
practice, and assuring competency rather than curricular completion.
THE ROLE OF THE ADDICTION

MEDICINE PHYSICIAN
The newly recognized field of addiction medicine is embracing these needed
changes in medicine as it prepares a physician workforce to assure that all
patients receive prevention and early intervention services and effective
treatment and disease management for addiction and its many co-occurring
disorders. Addiction medicine physicians play four essential roles in this
process: providing clinical expertise in direct patient care and in consultation
with other providers in multispecialty and interdisciplinary settings; serving as
faculty and teachers to educate and train others; performing clinical and health
policy research; and functioning as change agents to speed the evolution of
needed reforms.
Within addiction medicine and focusing on the role of physicians as change
agents, the ABMS and ACGME competencies of systems-based practice and
professionalism are especially salient. Systems-based practice is the physician’s
ability to “demonstrate awareness of and responsibility to the larger context and
systems of health care” and to “be able to call on system resources to provide
optimal care” (16). Since unhealthy substance use and addiction are influenced
by societal and public policy forces, and impact upon most other areas and
disciplines within medicine, a systems-based approach is necessary.
The core ABMS and ACGME competency of professionalism includes
accountability to society. Addiction medicine physicians can effectively employ
this competency by bringing attention and quality care to SUD at a level
consistent with the attention medicine gives to other medical conditions.
Physicians dedicated to the health of individual patients and families are also
ethically obligated stakeholders in health promotion for communities and larger
populations.
Some physicians eschew these aspects of medical competencies as
“politics,” believing that they do not apply to their own practice of medicine.
However, it has been wisely stated that “medicine is a social science, and politics
is nothing more than medicine on a larger scale” (17). The field of social
medicine, not to be confused with socialized medicine, posits that social and
economic conditions profoundly impact health, disease, and the practice of
medicine; that the health of the population is a matter of social concern; and that
society should promote health through both individual and social means (18).
Conversely, a disease state such as addiction also profoundly and adversely
impacts society.
One aim of social medicine includes physician promotion of “social justice”
through the reduction of health disparities or inequities deriving from “social
determinants of health”—the social, environmental, cultural, and physical
factors that different populations are born into and which impact childhood
development and adult maturation (19). These factors are often key determinants
in the use of addictive substances, in the medical and social consequences of
their use, and in the opportunities for medical and social interventions available
for prevention, treatment, and recovery. Some practices an addiction medicine
physician can employ to fulfill his or her role in this regard are reviewed later in
this chapter.
TRANSFORMATIONAL CHANGE
The old adage that a “Band-Aid approach won’t fix this problem” clearly applies
to the unsuccessful efforts of medicine and health care to attenuate the morbidity
and mortality associated with unhealthy substance use and addiction. Medicine,
healthcare systems, and key stakeholders are now being challenged to produce a
thorough and dramatic change in the form, character, and appearance of the
antiquated interventions, or complete lack thereof, necessary to address
unhealthy substance use and addiction. As the 21st century gets under way, we
are entering an era ripe for transformational change in the prevention and
treatment of SUD.
Transformational change (20) derives from a radical divergence from the
underlying consciousness, strategy, and processes that an organization or system
has been using. It can be identified by a shift in the culture of an organization,
field, or population that results in new expectations and new practices. Examples
include the near-total restriction of tobacco smoking in public places as well as
more private venues, the removal of all tobacco products from major health and
drug stores, and the acceptance of routine vaccinations. The United States is now
witnessing the emergence of another transformative shift of consciousness: that
addiction is a disease and not a character, moral, or criminal problem. Addiction
medicine physicians are challenged to lead, contribute to, and actualize strategies
and processes driving system changes to reflect this new public and medical
reality. Physicians are the ultimate purveyors of messaging and action in this
arena because SUD are medical disorders impacted by genetics and
environment, and these same medical disorders significantly impact human
environment and society.
America’s current acute care health system resulted from transformative
change triggered by the 1910 Flexner report (21). This report was the basis for a
sweeping reform and renewal of American medical education and practice.
Physician training was increased to a minimum of 6-8 years post secondary
education, medical research adhered to the protocols of the scientific method,
physician training itself was restructured in a scientific manner, literally half of
all medical schools were closed, and the state regulation of physician education
and practice was instituted. These changes—substantial improvements at the
time—were fundamental and have remained dominant and are accepted as
unalterable.
The need for a new shift from an acute care model to one that attends to the
full continuum of care from prevention and early intervention to chronic disease
management now demands a transformation of similar magnitude to that
initiated by Flexner over a century ago (22). Nowhere is this more obvious than
with the prevention and treatment of unhealthy substance use described
throughout this text.
Transformational change involves breakthroughs and challenges. In the last
20 years, the science of addiction and the evidence base for prevention and
treatment have increased significantly. Both the need and the challenges for
disseminating and implementing the science and evidence base are starkly
apparent to health professionals and others. Physicians can and must take a lead
in the campaign for modernization of care for these disorders.
A key prerequisite for transformational change is its dependence on
leadership that integrates and models the change being sought. If physicians
were still using tobacco in large numbers, how would that have impacted the
public health campaign for reducing the prevalence of tobacco use and related
disease? If physicians seek to work across traditional boundaries with other
stakeholders, here too by working collaboratively, they can both model a
winning strategy and improve the health of patients and our nation. In this, they
can lead. In fact, the skills physicians use so well in the clinical care of patients
to positively accentuate and promote the benefits of personal change are needed
now to achieve advancement in structure and cooperation between
interdependent elements in healthcare systems.
Finally and most importantly, transformational change engages the heart.
Science, economics, analysis, and critical thinking are necessary yet insufficient
to produce lasting changes in behaviors and the collective consciousness. And
just as they are in the care of the patient, these are all key drivers of positive
changes in systems. Systems are driven by individuals who interact, cooperate,
and collaborate with one another. We are not computers or robots. We are driven
by our aspirations, by issues, and activities we deeply care about that give
meaning to our lives.
To actualize system change, addiction medicine physicians armed with the
science of addiction and knowledge of best practices for reform have much to
offer. The Institute of Healthcare Improvement has promoted and validated the
well-known Plan-Do-Study-Act cycle, which breaks the change process into
straightforward steps (23). The detail of these steps is incorporated into the
content below and illustrated with the case of Dr. Smart.
A PROVEN APPROACH TO EFFECTING

CHANGE IN HEALTH CARE
1. Take a systems approach.
2. Put together a diverse, multidisciplinary team.
3. Develop a shared purpose and plan of action.
4. Act.
5. Evaluate, improve, repeat.
1. Take a Systems Approach.

A system is a set of interdependent elements interacting to achieve a common
goal (24). Physicians know or can learn the elements and processes in the
systems in which they are matriculating and can engage in interactions for
improvement. Cooperation (interaction) across traditional boundaries is not as
daunting a barrier as often perceived for physicians seeking system change.
Medical specialties, other health professions, and system managers often operate
in “silos of excellence.” Administrators, financial stakeholders, policy makers,
the public, and other interest groups also have their own “world views,” goals,
and preferred practices. Although a physician entering this larger system may
initially feel intimidation or hesitation, most newcomers will find this a
welcoming environment. In this milieu, physicians have a unique capacity to be
accepted as participants and critical leaders in improving healthcare systems and
advancing the quality of care for their own patients and many others. Physician
leaders holding the precept “do what is best for the patient” can bring quality of
care into discussions where other outcomes may dominate. Physicians, and
particularly addiction medicine physicians, have been absent or scarce in
deliberations at nearly every system level due to a limited workforce,
overwhelming patient care considerations, or the assumption that “someone is
working on this.” Key decisions on the care of patients thus have often excluded
effective input from addiction medicine physicians and defaulted to stakeholders
with more parochial interests.
An effective physician leader first examines the existing situation, then
imagines possibilities, and seeks a process and a plan for improvement. He or
she can participate in changing the system shortcomings or in creating a new
system. There are several realities physician leaders can recognize early:
leadership is an action, not a position; leadership is not victimhood—you cannot
be a leader and a victim simultaneously; leaders define reality—with data;
leaders develop and test changes; leaders take risk and have courage, because
complacent or threatened persons or organizations may react loudly and
negatively to a proposed change; leaders must cross boundaries, stepping outside
and letting go of defending their silo; and physician leaders seek and achieve
new interactions with a diversity of stakeholders (25).
Dr. Smart’s Emergence as a Change Agent

A family medicine physician we will call Dr. Smart works in a large hospital and
clinic system and was frustrated because she could not receive referrals and
assistance in a timely manner for her patients in need of acute substance use
disorder services, including consultations, and accepted level of care placements.
Depending on the immediate patient need, her frustration might come from the
hospital’s medical–surgical charge nurse (we have a lot of very sick patients
right now, we are too busy to take care of a person with an alcohol use disorder
or person with drug addiction), the system’s pharmacy (our protocol is for our
medical director to review the patient’s history, current diagnosis, and a
psychiatry consult before we dispense the medication you requested), the billing
and utilization office (your patient in withdrawal is no longer suicidal, you will
have to discharge him today), from one of her system physician colleagues (why
do you go overboard for these patients when they are not interested in helping
themselves), or from a patient’s family (my 17-year-old daughter has seen you
twice asking for help, why isn’t her drug problem being addressed?). In fact,
these are not uncommon situations, usually deriving from stigma, ignorance, and
outmoded and inefficient care systems. The family physician could address one
individual or service at a time—and ultimately all the staff in those departments
—to educate them about the disease of addiction and the modern treatment of
SUD. Yet that might not be productive. Taking a systems approach would
involve all of the key stakeholders and be a better use of her time and energy
toward long-term, integrated, and mutually appreciated solutions. As a
physician, she can go to system’s medical director or as far up the chain of
administration as possible, state her concern clearly, acknowledge that it is an
imperfect world yet that improved patient care and reduced system cost are
everyone’s goal, and within reach if addressed department or system wide.
This physician becomes a change agent and a physician leader the day she
speaks with an authority or “lever puller” within the system. Along the way, she
must be an effective communicator and teacher because from the lower echelons
to the highest in health systems, education of the stakeholders in essential. Now
Dr. Smart needs to be both an advocate for her patients and an advocate for
system change. To do that, she must become an enduring champion for change.
A single phone call or visit with the medical director or head nurse will not
suffice. Instead of complaining to the pharmacist, pleading with the charge nurse
or cursing utilization review, her approach to system change mimics her
approach to patients: they deserve care for their ailments, optimization of their
functioning, and attention to their ongoing well-being. Dr. Smart’s job is to let
system stakeholders know change is possible, to assist them, and to collaborate
with them, and it will take time. Now that she has the attention of system “lever
pullers,” what is next? Read on.
2. Put Together a Diverse, Multispecialty, Interdisciplinary Team.
Transformational change needs a broad set of participating stakeholders, from
both the internal and external organizational environments, who can collaborate
with each other. It requires inclusion and collaboration by diverse and multiple
stakeholders: from medicine and all disciplines, including nursing and other
health disciplines; from financial, governmental, and policy players; from
patients and the public. Health care affects all Americans. It is one of our highest
national values and impacts all aspects of public and social health. It is central to
the successes and failures of American society and culture. We all own it, and
we must all participate in improving it. Every addiction medicine physician has a
contribution he or she can make.
Multispecialty (physicians from different medical specialties),
interdisciplinary teams provide for a group of healthcare professionals from
diverse and complimentary fields who work together toward a common goal;
ideally accelerating a cooperative environment. Physicians can assume the role
of champion, but they do not always have to be the team leader; they can assume
a mentoring role by modeling listening skills, openness to change, willingness to
make suggestions and continued participation on the team. Physicians should
expect and encourage a diversity of styles—most healthcare professions have
their own cultures and values, and the reality is physicians do not own the single
standard. Stakeholders who are involved in the process of change are more likely
to be cooperative if they sense openness instead of resistance when offering a
view, which varies from physicians’ traditionally authoritarian stance of having
the ultimate answer. When meeting with nonphysicians, the pool for ideas and
suggestions can be expanded when the physician or group leader asks each
person for his or her concerns and opinions. Inclusion of freely expressed and
diverse ideas from a group of interdisciplinary stakeholders accelerates a
cooperative environment.
Dr. Smart Plots a Course
Dr. Smart was not discouraged by the reception she received from her superiors
in the health system. They listened patiently, agreed that things could be
improved, and in a pleasant tone suggested she speak with individual department
chiefs and persons she perceived as obstacles to better care for her patients.
Having already had nonproductive individual conversations with the subject
departments and staff, she decided to bring all the players together. For 6 weeks,
she “socialized” the idea of an intradepartment meeting and sought out
sympathetic or at least open-minded staff to participate in an opening dialogue.
She designed a 60-minute lunch time meeting titled “Introduction to Standards
of Care for Patients with Unhealthy Substance Use and Addiction.” Key leaders
and staff from all departments were invited, as well as clinic and hospital staff
physicians (medical, surgical, behavioral health services, ED, and critical care
units). She also invited external stakeholders including community treatment
programs, the county health officer, and substance use professionals. For an
agenda, she first gave a 10 slide overview of SUD, levels of care, and state of the
art prevention and treatment modalities. Next, she facilitated very brief
statements from willing and prepared representatives from nursing, pharmacy,
social services, behavioral health, and 2 other physician champions from the
obstetrical and internal medicine staff. The session was well attended. At the
close, she asked how many attendees thought that additional sessions and
discussions would be useful. She signed up 16 panelists and attendees to meet
again in a month. Dr. Smart now had the beginnings of a multispecialty,
interdisciplinary team.
3. Develop a Shared Purpose and Plan of Action.
Human systems derive their identity from a shared, common purpose. The
dialogue of change thus begins with the question, “What are we trying to
accomplish?” And to engage the passion of the participants asks, “Why is this
important to you?”
It is crucial to develop and gain consensus on the purpose and aim of the
desired improvement, enlisting and aligning as many stakeholders as necessary
or possible to consider alternatives to the status quo. State clearly the testable
objective of the plan. The “aim” of the desired improvement should be time
specific, measurable, and define the patients, populations, and system(s) to be
involved. The Institute of Medicine has suggested that there are six broad
categories for most desired improvements: safety, effectiveness, patient
centeredness, timeliness, efficiency, and equity.
Detail the components of the plan, remembering you may be starting small,
and develop quantitative measures, which can be used to monitor and calculate
the outcome. With the outcome data, it can be determined whether the plan
resulted in an improvement. As a physician leader, your own commitment and
endurance are essential. Physicians who desire and work for change that will
result in a system’s improvement become knowledgeable and gain experience in
making small improvements and always cooperate with others. They start with
small goals and objectives and seek collaboration. Defined rules are a critical
attribute of a cooperative environment.
This is a group process, since persons both within and outside of the
departments or organization have varying experience on the system elements
involved and can suggest change concepts from which a proposed single change
is chosen. No change effort will succeed without cooperation. Cooperative
interactions may be ethical and altruistic, yet they are a prerequisite and
pragmatic strategy for engineering change in interdependent systems.
Effective leaders learn, model, and teach expertise in basic dialogue and
group communication. Basic negotiation attitudes and skills are requisite for
success and can be acquired from reading or courses. Success is more likely
when the decision process focuses on issues and not individuals and empowers
ownership in the change process and results. The frequently expressed complaint
that nothing will change until “that person moves on” is counterproductive.
There are always issues that can be win–win for all parties. Change is dependent
on new solutions, not lamenting current shortcomings.
Dr. Smart and the SUD Standards of Care

Team
At the first meeting of the self-identified team, also over lunch, there was a
broad and often divergent range of concerns expressed. Dr. Smart facilitated the
meeting and made sure everyone was able to state their issues regarding the care
of patients with SUD. As attendees spoke, she used a whiteboard to categorize
and list the issues presented. She titled the sections: safety, effectiveness, patient
centeredness, timeliness, and efficiency. The group then began meeting weekly.
By the 6th week, the self-named SUD Standards of Care Team had produced a
list of five system changes that all agreed would be beneficial and could be
accomplished: routine application of screening; brief intervention and referral to
treatment (SBIRT) in the system’s adult primary care; urgent care and
emergency departments; routine use of the Screening to Brief Intervention
(SB2I) tool (26) for patients ages 12-21; an available counselor to assist with
BIRT when indicated; a warm hand-off to a social worker to assure a confirmed
“bridge” to the indicated level of SUD treatment for patients needing more than
a brief intervention; and immediate availability of medications from the
pharmacy when requested by physicians and other providers identified as
members of the SUD Standards of Care Team. A document with the targeted
changes and a detailed plan for implementing them and evaluating the results
was vetted by the group over several meetings. Team representatives then
brought their proposal to the health system leader with whom Dr. Smart had met
with 3 months earlier. She was impressed that personnel from various
departments had worked together on the proposal and agreed to set a meeting
with the team representatives and system department–level leaders who would
need to endorse and oversee implementation of the proposal. This was
accomplished 4 weeks later with a consensus that the objectives of the team
were reasonable and the plan could be implemented and tested.
4. Act.
With a detailed plan in place and the assurance that the people, procedures, and
processes needed to execute it are in place, and after all stakeholders—including
patients if they are involved—are onboard, begin on a planned start date.
Dr. Smart’s Initiative Gets Traction

Dr. Smart set another system-wide informational meeting where the team and the
critically involved system leadership and administrators outlined the rationale
and objectives for the plan of improvement, with a detailed timeline,
responsibilities, and evaluative methodology. The implementation start date was
announced at the meeting and subsequently through multiple health system
communication paths. The meeting was attended by 75 internal and external
stakeholders and interested staff.
5. Set Up a Strategy for Evaluation and Improvement.
Monitor key aspects and measures for the plan, document problems and
unexpected observations, and begin preliminary analysis of the data. Recall the
saying “what get measured gets done,” and remember that there is no innovation
without data. Take the time and engage the people and system elements that the
cycle will involve or impact.
At appropriate and strategic intervals, analyze the emerging data. Compare
them with your predictions and discuss with the team, reflecting on what was
learned. Determine what modifications should be made and prepare a plan for
next steps.
The SUD Standards of Care Team Follows

Through
Implementing the four overlapping objectives of the plan had some early bumps
and unexpected consequences. Modifications were made. At the 3-month
evaluation mark, the predetermined evaluative indices were reported: repeat
visits and readmissions through the ED decreased, intensity of laboratory and
other diagnostic and care services for substance using patients decreased, and the
number of clinic patients entering community-based outpatient treatment and the
use of appropriate medications increased. A survey of involved system staff
indicated that they believed the changes had improved patient care,
communication, and morale. The various departments and the care providers
who were directly caring for the patients indicated that they were both satisfied
with the results of the changes. The administration presented data showing that
there was no increased cost associated with the changes and likely a savings in
several departments and expense categories. A predesigned patient survey
indicated that those who received services under the new changes were highly
satisfied.
The SUD Standards of Care Team Becomes

Institutionalized
The SUD Standards of Care Team continued to meet regularly and address other
system-based modifications to improve quality care and reduce costs. Eighteen
months after Dr. Smart’s first meeting with the system leadership, she was
approached by the health system’s Medical Director, its CEO, and the Chair of
the Family Medicine Residency and asked to consider establishing an ACGME
accredited addiction medicine fellowship, for which the health system would
provide funding and other support.
SUMMARY
Unhealthy substance use impacts people we work with, live with, and those with
whom we share community; persons we care about; and those we love. On some
level, it is personal for all of us. Foremost, health care is much more than a
calculated business venture; it is compassion and caring for all with whom we
are connected. Every addiction medicine physician is needed to bring
prevention, high-quality treatment, and systems improvement into reality.
Addiction medicine can lead and contribute to the well-being of communities
and nations as well as to our patients and their families. Whether physician
contributions are made in assessing, planning, and acting on improvements in a
small clinic, a large healthcare system, or at the level of governmental policy
impacting public health, this is all within the mission and character of the field
of addiction medicine. Addiction medicine physicians are clinical experts,
faculty and teachers, researchers, and change agents. This is our work and we
can succeed.
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SECTION 2
Pharmacology
CHAPTER 8
Pharmacokinetic, Pharmacodynamic,
and Pharmacogenomic Principles
Lori D. Karan and Anne Zajicek
CHAPTER OUTLINE
Introduction
Basic Pharmacology Concepts
Summary
INTRODUCTION
Pharmacotherapy in the clinical practice of addiction medicine is based on the
application of pharmacological principles to ease the suffering from addiction to
various addictive substances and behaviors. Pharmacological principles in this
chapter will focus on the pharmacokinetics of drug delivery to the brain and
placenta; pharmacogenomics, the genetic differences in metabolism, transport,
and receptors that effect interindividual differences in drug disposition and
response; and pharmacodynamics effects including tolerance and withdrawal.
BASIC PHARMACOLOGY CONCEPTS

Pharmacokinetics
Pharmacokinetics describes the time course of drug concentrations in blood and
tissues (eg, , brain). Drug concentrations in blood and other sites are determined
by absorption, distribution, metabolism, and elimination. The magnitude of a
drug’s pharmacological effect depends on the free (unbound) drug concentration
at its site of action.
Absorption
Absorption is the process of drug movement from the site of drug delivery to the
site of action. Psychoactive drugs can be taken orally (ethanol, amphetamines,
barbiturates, opioids), intranasally (glue, solvents, amyl nitrate, cocaine, heroin),
via smoking (combusted versus vaporized and then aerosolized sources of
nicotine, marijuana, freebase cocaine), intravenously (heroin, cocaine,
methamphetamine), transdermally (fentanyl and nicotine patches), and by
subcutaneous injection. Figure 8-1 illustrates the differences in drug
concentrations over time for the various routes of administration. The more
rapidly a psychoactive drug is delivered to its site of action in the central nervous
system, the greater are its reinforcing effects. The more rapidly achieved and
higher peak concentrations from intravenous and pulmonary (smoking) routes
illustrate this point.
Figure 8-1 Venous drug concentrations after different routes

of administration.
Bioavailability is defined as the fraction of unchanged drug that reaches the

systemic circulation after administration by any route. The bioavailability factor
(F) takes into account the portion of the administered dose that is able to enter
the circulation unchanged. For intravenously administered drugs, F = 1.0
(100%). Bioavailability depends on a given drug’s site-specific membrane
permeability, activity of drug transporters, and its first-pass metabolism. First-
pass metabolism is the metabolism that occurs before a drug reaches the
systemic circulation. It occurs most extensively for lipid-soluble drugs such as
morphine, methylphenidate, and desipramine and can significantly reduce
bioavailability. Morphine, for example, requires nearly twice the dose when
administered orally as compared to intravenously. First-pass metabolism is
relatively unimportant for drugs administered through the intravenous,
sublingual, intramuscular, subcutaneous, and transdermal routes, since drugs
administered by these routes enter the general circulation directly.
For orally administered drugs, the rate of absorption is affected by (i) the
pharmaceutical properties of the oral dosage form, for example, immediate
versus extended release formulation; (ii) the pH of gastric contents (drugs can be
destroyed by extreme acid or basic conditions); (iii) gastric emptying time (faster
gastric emptying time results in more rapid delivery to the small intestine, the
site of absorption, except with dumping where the delivery to the small intestine
is too fast to be optimally absorbed); (iv) intestinal transit time (for drugs
absorbed in the small intestine, there is an decreased rate of absorption with a
faster intestinal transit time); (v) integrity of intestinal epithelium; and (vi) the
presence of food (which decreases the interaction time between the drug and the
intestinal villi) (1).
Efforts have been made to reformulate potentially addictive prescription
drugs to reduce the rates of absorption in order to reduce the peak concentrations
and reduce this reinforcing effect (2).
Intranasal drug administration holds promise not only for medications with a
local effect on the nasal mucosa but also for potent medications with systemic
activity such as peptide hormones and antimigraine medications. The nasal
cavity is covered by a thin mucosa, which is well vascularized. Local anesthetics
such as cocaine are vasoconstrictive and limit their own absorption. Once
transferred across the single epithelial layer of the nasal mucosa, drug molecules
directly enter the systemic blood circulation without undergoing first-pass
metabolism. In addition, the central nervous system activity of intranasal
naloxone may be enhanced via absorption through the cribriform plate high in
the nasal cavity as well as via the olfactory and trigeminal nerves (3).
Smoked and inhaled drugs bypass the venous system and thus have the most
rapid rate of delivery. Absorption of inhaled drug depends on the physical
characteristics of the drug, including its volatility, particle size, and lipid
solubility (4). Drugs that reach the alveoli of the lungs have rapid access to the
bloodstream through closely applied capillary alveolar surfaces on the large
pulmonary surface areas. Because a large portion of the cardiac output passes
through the pulmonary circulation, both smoked nicotine (including its freebase
form) in cigarettes and freebased cocaine are examples of highly reinforcing
drugs that are rapidly delivered to the brain.
Drugs must pass through biological membranes to be absorbed. With passive
diffusion, biological membranes are more permeable to lipid-soluble and
uncharged molecules. Some drugs have diminished absorption because of a
reverse transporter associated with P-glycoprotein. This reverse transporter
actively pumps drug out of the gut wall cells back into the gut lumen. When P-
glycoprotein is inhibited, increased drug absorption results.
Some food and drug interactions alter first-pass metabolism and absorption
from the intestinal wall. For example, components of grapefruit juice and other
foods that either inhibit (eg, grapefruit juice) or induce intestinal wall CYP3A4
or P-glycoprotein can lead to altered bioavailability of drugs that are substrates
for this cytochrome (5,6). Also, the nonselective monoamine oxidase inhibitors
(MAOIs) such as phenelzine and tranylcypromine—and, to a much lesser extent,
the MAO B inhibitor selegiline and the reversible MAOI moclobemide—inhibit
MAO A in the intestinal wall and liver. This inhibition diminishes the first-pass
metabolism of tyramine, which is present in cheeses and various foods such as
cured meats and yogurt in which protein breakdown is used to increase flavor
(7). When tyramine, an indirect-acting sympathomimetic amine, reaches the
systemic circulation, it can produce increased release of norepinephrine from the
sympathetic postganglionic neurons; this, in turn, can result in a severe pressor
response and hypertensive crisis.
Hastening gastric emptying can help to achieve a more rapid drug effect
without altering bioavailability. Taking a drug on an empty stomach with at least
200 mL of water and remaining in an upright position can speed gastric
emptying. Food, recumbency, heavy exercise, and drugs that slow gastric
emptying (such as narcotics and anticholinergic drugs) can result in later and
lower peak concentrations of the index drug.
Upon absorption, when drug concentrations are graphed against time, a peak
drug concentration (Cmax) is reached at Tmax. The trough concentration is Cmin.
The area under the concentration–time curve (AUC) is a measure of drug
exposure that can be calculated and quantified.
Distribution
Once absorbed, a drug is distributed to the various organs and tissues of the
body. Distribution is influenced by organ perfusion, organ size, binding of the
drug within the blood and tissues, and the permeability of tissue membranes (8).
Most psychoactive drugs enter the brain because they are highly lipid
soluble. The blood–brain barrier hinders the ability of non–lipid-soluble drugs to
reach the brain tissue by diffusion (9). Unlike the fenestrated capillaries found
throughout the body, which allow movement of molecules <25,000 Daltons, the
endothelial cells lining brain capillaries have tight junctions and do not permit
these small molecules to pass through. Without fenestrations, drugs must cross
the two membranes of the endothelial cell by passive diffusion in order to enter
the brain. The blood–brain barrier limits the admittance of many drugs to the
brain and is found throughout the brain and spinal cord at all regions central to
the arachnoid membrane, except for the floor of the hypothalamus and the area
postrema, including the chemoreceptor trigger zone (where direct-acting
chemicals can provoke vomiting).
For some compounds, however, specific active transport systems exist.
These active transport systems enable glucose, amino acids, amines, purines,
nucleosides, and organic acids to gain access to the brain (10). In contrast, P-
glycoprotein is an efflux carrier present in the brain capillary endothelial cell,
which bars the drug from translocating across the endothelial cell and actively
exports the drug out of the brain (11).
When a drug distributes into all of the body compartments and tissues, it is
said to distribute into an apparent volume of distribution (Vd). This volume has
no direct physical equivalent because it describes the amount of serum, plasma,
or blood that would be required to account for all the drug in the body. Vd can be
thought of as the amount of drug in the body (D = dose) divided by the
concentration of drug (C) in the plasma, or
Drugs with a small Vd are confined primarily to the intravascular space of ~5 L.

The drugs may be tightly bound to plasma proteins, or they may have a high
molecular weight (large proteins, dextrans, and so forth). Drugs can have large
Vd values up to 50,000 L if they are highly bound to tissue sites or are lipophilic.
Protein binding affects free (active) drug concentrations. Characteristics of
binding proteins are capacity (amount of binding space) and affinity (tightness of
binding interaction). Albumin is a high-capacity, low-affinity binding protein,
whereas specific transport proteins such as transcortin are low capacity, high
affinity. Acidic drugs commonly bind to albumin, the most abundant plasma
protein; examples are barbiturates, benzodiazepines, and phenytoin. Basic drugs
such as methadone bind to alpha1-acid glycoprotein, and others such as
amitriptyline and nortriptyline bind to lipoproteins. Some binding sites are
competitive, and a drug with a higher binding site affinity can displace a drug
with a lower binding site affinity. Binding can also be stereospecific (specific for
one stereoisomer of a compound). Drugs that are >90% bound are considered
highly protein bound, and reduced protein binding for these highly protein bound
drugs can lead to large increases in drug effect.
The rate of blood flow delivered to specific organs and tissues affects drug
distribution. Well-perfused tissues can receive large quantities of drug, provided
that the drug can cross the membranes or other barriers present between the
plasma and tissue. In contrast, poorly perfused tissues, such as fat, receive and
release drug at a slow rate. This action explains why the concentration of drug in
fat can be maintained long after the concentration in plasma has begun to
decrease; anesthetics are examples of this phenomenon. For example, since
women tend to have more body fat than men, the FDA recommended in 2013
and again in 2016 that women be prescribed half the dose of zolpidem. This
recommendation was because women were having increased car accidents the
morning after taking zolpidem.
Clearance
Elimination refers to disappearance of the parent and/or active molecule from
the bloodstream or body, which can occur by metabolism and/or excretion.
Excretion is the process of removing a compound from the body without
chemically changing that compound. Drugs can be excreted through the urine or
feces, exhaled through the lungs, or secreted through sweat or salivary glands.
The term clearance (Cl) represents the theoretical volume of blood or plasma
that is completely cleared of drug in a given period of time. The factors that
determine hepatic clearance are hepatic blood flow, the fraction of drug that is
unbound, and the drug’s intrinsic clearance. If the intrinsic clearance of an
unbound drug is very large, blood flow to the liver becomes rate limiting. If the
intrinsic clearance of an unbound drug is very small, then this metabolic capacity
(ie, intrinsic clearance) of the liver, rather than hepatic blood flow, becomes the
major determinant of hepatic clearance. In this case, activity of hepatic enzymes
determines drug clearance. Metabolic capacity determines drug clearance in
most cases.
Most drugs display first-order elimination kinetics: the fraction or
percentage of the total amount of drug present in the body removed at any one
time is constant and independent of dose. Following administration of a drug
with first-order kinetics, concentrations show an exponential decline of drug
concentrations. The slope of this decay line is the elimination rate constant, kel,
which is the percent of drug cleared per unit time (eg, percent/hour). The half-
life (t1/2) of a drug is the amount of time it takes for a drug concentration to
decrease by half. One half-life represents a 50% change, and 2, 3, 4, and 5 half-
lives represent 75%, 87.5%, 93.7%, and 96.8% changes, respectively. The time
to reach steady state depends upon the duration of the half-life, whereas the
amount of drug in the body at steady state will depend upon the frequency of
drug administration and its dose. With drugs with dose-independent (first-order)
disposition and elimination characteristics, five half-lives is a reasonable
estimate of the time to reach steady state. For example, if the concentration at 2
hours postdose is 100 μg/mL, and the concentration at 4 hours postdose is 50
μg/mL, the t1/2 is 2 hours.
One means of calculating t1/2 is
Using a more physiological approach, t1/2 is directly related to the volume of

distribution (Vd) and inversely related to the clearance (Cl). This relationship can
be written as follows:
The constant 0.693 in this equation is derived from the natural logarithm of two
[ln(2)]. Because drug elimination can be described by an exponential process,
the time taken for a twofold decrease can be shown to be proportional to ln(2).
Although it is reasonable to assume that t1/2 and clearance are inversely
related (clearance increases, so t1/2 decreases), effects of Vd on t1/2 do occur,
which can offset the change in Cl (Vd decreases by the same proportion as
clearance decreases, resulting in no change in t1/2).
In contrast, for drugs with zero-order elimination kinetics, the amount of
drug removed (rather than the fraction of drug removed) at any one time is
constant and dependent on dose. The maximal rate of metabolism and/or
elimination is generally due to saturation of a key enzyme. This zero-order
process is described by the Michaelis-Menten equation:
where v is the velocity of the reaction, Vmax is the maximum velocity of the
reaction, Km is the concentration of the metabolic substrate when the velocity is
½Vmax, and Cpss is the steady-state concentration of drug. In the case of linear
kinetics, Km is >>> Cpss, and v = Vmax × Cpss/(Km), or the v is proportional to
the drug concentration: the higher the drug concentration, the faster the velocity.
When Km <<< Cpss, v = Vmax, which is the case for drugs cleared by zero-order
kinetics; the velocity is limited by Vmax. Because the half-life is inversely related
to clearance, and clearance changes with drug concentration, the t1/2 is not
constant. Therefore, half-life is not a useful descriptor for zero-order drugs. Drug
dosing becomes difficult in these cases: a small increase in dose can cause a
large increase in concentration, in contrast to drugs with first-order clearance
where there is proportionality between dose and concentration. Aspirin,
phenytoin, and ethanol are examples of drugs with zero-order elimination (12).
See Figure 8-2 for a calculation of the decline in blood alcohol concentrations
over time, demonstrating zero-order kinetics.
Figure 8-2 Extrapolating the decrease in blood alcohol

concentration from two prior readings.
Expect at 4 hours BAL to be 55 mg/dL; 5 hours, BAL to be 35 mg/dL; 6 hours,

BAL to be 15 mg/dL; and 7 hours, BAL to have already reached 0.00 mg/dL.
Drug metabolism is the process of chemical modification of drugs and other
chemicals by the body, generally into less active and more hydrophilic
compounds. These chemical modifications/reactions are generally performed by
enzymatic systems, such as the cytochrome P450 (CYP) enzyme system.
Lipophilic drugs are generally transformed to more hydrophilic/polar products
that are more readily eliminated by the kidney. Not all metabolites are inactive or
nontoxic, and active metabolites need to be considered when assessing a drug’s
total activity. In some cases, the administered drug is intentionally designed to be
a pharmacologically inactive prodrug that is converted in vivo to a
pharmacologically active molecule. Levodopa is one example, which (after
crossing the blood–brain barrier) is converted in the basal ganglia to dopamine.
Drugs can be metabolized by phase I and/or phase II reactions. Phase I
reactions are nonsynthetic reactions in which the drug is chemically altered and
oxidized, for example, demethylated. Examples of phase I reactions include the
oxidation of phenobarbital, amphetamine, meperidine, and codeine by
microsomal enzymes. Phase II reactions are synthetic reactions in which the
drug is conjugated with another moiety, such as glucuronide or sulfate. Examples
of synthetic reactions include the glucuronidation of morphine and meprobamate
and acetylation of clonazepam and mescaline, which produce a compound more
polar than the parent drugs in order to facilitate elimination.
Enzymes are responsible for most drug metabolism. Cytochromes P450
belong to the superfamily of proteins that are bound to the membrane in a cell
(“cyto”), contain heme pigment as a cofactor (“chrome P”), and are often
terminal oxidase enzymes in electron transfer chains. When the enzyme is in a
reduced state and complexed with carbon monoxide, it has a 450-nm
spectrophotometric absorption maximum.
The CYP enzymes are most commonly involved and exist in the gut, liver,
and brain. The gut and liver enzymes are the best studied. Oxidations can take
place by CYP-dependent and CYP-independent mechanisms. CYP-dependent
oxidations include aromatic (phenytoin, amphetamine) and aliphatic
(pentobarbital, meprobamate) hydroxylations, epoxidation, and oxidative
dealkylation (morphine, caffeine, codeine), deamination (amphetamine),
desulfurization (thiopental), and dechlorination. CYP-independent oxidations
include dehydrogenations (ethanol); azo, nitro, and carbonyl reductions
(methadone and naloxone); and ester and amide hydrolysis (13).
More than 50 individual CYPs (pronounced “sip” for singular and “sips” for
plural) have been identified in humans. As a family of enzymes, CYPs are
involved not only in the metabolism of dietary and environmental compounds
and medications but also in the degradation of bile acids from cholesterol, the
metabolism of retinoic and fatty acids including prostaglandins and eicosanoids,
and the synthesis of steroids. A large number of specialized CYPs with specific
substrate preferences are involved in these latter endogenous functions, in
contrast to the relatively few numbers of CYPs that metabolize xenobiotics that
have wider ranging and overlapping capabilities. CYPs that metabolize
medications not only have a tremendous capacity to oxidize a large number of
structurally diverse compounds but also can metabolize a single compound at
different positions on that molecule. Drug-metabolizing CYPs’ large and fluid
substrate–binding sites contribute to their slow catalytic rates. In part, this
explains why the half-lives of drugs are much longer than the half-lives of
endogenous compounds.
CYPs are named with the root CYP followed by a number designating the
family, a letter denoting the subfamily, and another number designating the CYP
form. Thus, CYP2B6 is family 2, subfamily B, and gene number 6. Twelve
CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5)
are known to metabolize xenobiotics in humans, and CYP3A4 alone is
responsible for metabolizing more than 50% of clinically prescribed drugs.
Inhibition or induction of CYP3A4 is a major source of drug interactions. Many
commonly used medications induce or inhibit CYP3A4, creating clinically
relevant changes in drug clearance and clinical response. Other factors also
cause enzyme inhibition or induction: the polycyclic aromatic hydrocarbons in
cigarette smoke induce CYP3A4 (as well as CYP 1A1, 1A2 and 2E1) (14),
whereas grapefruit juice and several antiretrovirals inhibit 3A4. Other significant
drug interactions occur with antidepressants such as bupropion and fluoxetine,
which inhibit CYP2D6 (15).
Pharmacogenomics
Pharmacogenomics is the study of the relationship between genetic variations
and drug disposition and response. The discipline of pharmacogenetics aims to
elucidate cytochrome and other drug-metabolizing enzyme polymorphisms
(different enzyme genetic subtypes), the degrees of expression of these
polymorphisms, and the functional significance of such expression.
Understanding these polymorphisms can help to explain individual differences in
drug response.
Genetic variability in drug-metabolizing enzymes can affect drug
bioavailability and clearance (16–19). Single nucleotide polymorphisms (SNPs)
may alter CYP activity. CYP2D6, for example, which metabolizes codeine to
morphine, is the best studied of the drug metabolic enzymes; 109 alleles and
numerous mutations have been identified (20). Genotype and enzyme activity
are linked to ethnicity, which varies from no gene/no enzyme activity (6% of
whites) to two copies of a fully active gene (33% of Ethiopians). Individuals can
be genotyped for 2D6 enzyme function (with classification as poor metabolizers
[PMs], intermediate metabolizers [IMs], extensive metabolizers [EMs], and
ultrarapid metabolizers [UMs]) (21). Those with PM genotypes generally do not
receive adequate analgesia due to the inability to metabolize codeine to the
active morphine. UMs, on the other hand, metabolize codeine significantly more
rapidly and extensively than others, producing rare but life-threatening morphine
intoxication. Breast-feeding infants of mothers who are UMs have received
morphine overdoses from their mothers who are prescribed codeine for
postpartum pain relief (22,23).
CYP2B6 has been less well studied (24). However, important genotypic
influences on enzyme function have been identified. For instance, the *4 allele,
which codes for an enzyme of higher function than the wild type, has been
associated with the toxicity of bupropion due to increased rates of conversion of
bupropion to the active and longer-lasting metabolite, hydroxybupropion. Zhu et
al. found that increasing the dose of hydroxybupropion (but not to the point of
toxicity) in PMs could improve tobacco abstinence rates (25,26)
As pharmacogenetic testing becomes less costly, studies to determine the
evidence for the use of these tests are growing. Right now, identifying CYP
isoforms is mostly done on a retrospective basis to understand unusual drug
responses. The future holds promise for more personalized prescribing (27).
Prior to the more routine availability and use of genotyping, phenotyping of
CYPs using marker compounds has been, and continues to be, a useful tool. A
“cocktail” approach has been used, where subjects are administered microdoses
of various compounds, each of which are metabolized by one specific enzyme
and would reflect the enzymatic activity for clinically used medications. There
are many “cocktail” recipes, one of which is the six-probe cocktail consisting of
caffeine (1A2), flurbiprofen (2C9), mephenytoin (2C19), debrisoquine (2D6),
chlorzoxazone (2E1), and dapsone (NAT2), where NAT2 is N-acetyltransferase
2 (28,29).
Drug interactions at the level of the cytochromes and other metabolizing
systems are often clinically significant. Methadone is metabolized primarily by
CYP3A4, with contributions from CYP2B6, 2C19, 3A4, and, to a lesser extent,
CYP2D6 (30). Inhibitors of CYP3A4, including erythromycin, diltiazem,
ketoconazole, and saquinavir, slow the metabolism of methadone and increase
methadone levels. Inducers of CYP3A4 such as carbamazepine, phenobarbital,
efavirenz, and St. John’s wort speed the metabolism of methadone and decrease
methadone levels (31). Awareness of potential interactions, clinical observation,
and tailoring medication regimens and dosages are needed to optimize therapy
and minimize potential toxicities.
Genetically defined differences in drug metabolism may influence risk of
addiction, with relative protection for persons who experience adverse drug
reactions at lower drug doses. Both the ADH1B2-His47Arg allele of alcohol
dehydrogenase 1B and the ALDH-Glu487Lys allele of aldehyde dehydrogenase
2 alone or together can lead to flushing, nausea, and headache, owing to the
accumulation of acetaldehyde when alcohol is consumed. Each of these alleles
leads to a reduction in the risk of alcohol use disorder, with an additive
protective effect when the same person carries both alleles. Persons of South
Asian descent are likely to carry both alleles, whereas those with Jewish ancestry
often carry the Arg47 allele. Heterozygous carriers of ALDH2 Lys487 have low
levels of ALDH2 enzyme activity, whereas ALDH2 Lys487/Lys487
homozygotes are nearly completely protected from alcohol use disorder (32).
Tyndale et al. (33) were among the first to postulate the existence of
“pharmacogenetic protection factors.” They showed that a sample of whites who
inherited two nonfunctional alleles for CYP2D6 were less likely to become
addicted on oral opioids (estimated odds ratio > 7). Slow nicotine metabolism by
CYP2D6 to cotinine appears to have a protective effect against nicotine
addiction (34).
Although drug metabolism occurs largely in the liver, most other tissues and
organs, including the lungs, gastrointestinal tract, skin, and kidneys, carry out
varying degrees of drug metabolism. Understanding brain metabolism can be
especially important in understanding the activity of psychoactive drugs (35,36).
Drug-metabolizing enzymes are located at blood–brain interfaces where they
form an “enzymatic and metabolic barrier.” Variation in Cyp450 expression in
the neuronal and glial cells in different brain areas may help explain differences
in individual response to psychoactive substances and their treatments. Many
P450 cytochromes have been shown to catalyze the metabolism of neurosteroids
as well as psychoactive drugs such as neuroleptics and antidepressants. Alcohol
produces a three- to five-fold increase in the level of brain P450 and induces
CYP2C, CYP2E1, and CYP4A (37). Brain CYP2D6 can demethylate 3,4-
methylenedioxy-N-methylamphetamine (MDMA or “ecstasy”) forming a
harmful metabolite, N-methyl-a-methyldopamine. Brain CYP2D6 can O-
demethylate para-methoxyamphetamine, a synthetic psychostimulant and
hallucinogen, into 4-hydroxyamphetamine, which is also toxic (38). P450s in
other brain areas are induced by different factors (eg, levels of CYP2C and
CYP4A influence the activity of neurotransmitters such as dopamine, which use
fatty acid metabolites as intracellular mediators).
Novel brain CYPs, such as 5α-androstane-3β, 17β-diol hydroxylase,
CYP7B, and CYP2D4, continue to be discovered (39,40). Because the level of
CYPs in the brain is approximately 0.5%-2% of that in the liver and because
brain CYP isoenzymes are of different types than those found in the liver, brain
CYPs appear to be locally active but contribute little to overall pharmacokinetics
of drugs in the body. The regulation of CYP isozyme expression in the brain and
elsewhere is being studied.
New areas of research include studies demonstrating novel brain transporter
pathways (41). Epigenetic factors (42) and use of genome-wide association
studies (43) may also yield new insights.
Pharmacodynamics
Pharmacodynamics is the study of the dose–response phenomena, which are the
biochemical and physiological effects of drugs on the body, and the body’s
homeostatic response. Most drugs act on specific endogenous targets, or
receptors, to modulate the rate and extent of the body’s endogenous functions.
Receptors and their associated effector and transducer proteins coordinate
signals from multiple ligands with the metabolic activities of the cell to act as
integrators of this information.
Potency, Efficacy, and Dose–Response

When drug dose is plotted on a logarithmic scale, a sigmoidal curve often
results, permitting mathematical manipulation of the results. The maximal
efficacy of a drug occurs at Emax, its maximal effect. Efficacy is the extent of
functional change imparted to a receptor. Efficacy is determined mainly by the
nature of the receptor and its associated effector system. In contrast, potency is
primarily determined by the affinity of the receptor for the drug. Potency denotes
the amount of drug needed to produce a given effect. The concentration of the
drug needed to produce 50% maximal effect occurs at EC50; the more potent the
drug, the smaller the dose required to achieve a given effect. In general, low
potency is important only if the drug needs to be administered in undesirably
large amounts. Because drug doses are readily adjusted, it is the maximal
efficacy that is more often clinically relevant.
A similar sigmoidal curve is attained when the percentage of receptors that
bind a drug is plotted against log drug concentration (Fig. 8-3). Here, the
concentration at which 50% of the receptors are bound is denoted as Kd, and the
maximum number of receptors bound is termed Bmax. Both “dose–response” and
“dose–receptor-bound” graphs have a linear or nearly linear middle segment,
indicating a first-order process. As the concentration of drug increases, a
constant proportion of the drug binds to the receptor, causing a proportionate
drug effect.
Figure 8-3 Full agonist, partial agonist, and competitive and

noncompetitive antagonists. A: No matter how much the
dose is increased, a partial agonist always will have a lower
maximal efficiency (Emax). A partial agonist may be more
potent, less potent, or equally potent as the agonist. In this
example, both partial agonists decrease Emax. However, one
partial agonist is more potent, and the other partial agonist is
equipotent, when compared to the full agonist. B: If there are
no spare receptors, competitive agonists increase the EC50
but do not alter the other Emax. C: Noncompetitive
antagonists decrease the Emax. (Modified from Katzung BG,
Masters SB. Pharmacodynamics. In: Katzung and Trevor’s
Pharmacology Examination and Board Review. New York,
NY: Lange Medical Books/McGraw-Hill, 2002:13.)
A system is said to have spare receptors when the activation of fewer than 50%
of the receptors achieves 50% of maximal effect. This determination is made by
comparing the concentration for 50% of maximal effect, EC50, with the
concentration of 50% of maximal binding, Kd. If the EC50 is less than the Kd,
spare receptors are said to be present. The presence of spare receptors does not
alter the maximal biological response, but it does increase the sensitivity to the
drug ligand. This relationship occurs because drug–receptor interactions are
more likely to appear when there are proportionately more available receptors.
A graded dose–response graph is attained (Fig. 8-4) when the response of a
particular receptor–effector system is measured against increasing concentrations
of drug. A quantal dose–response graph is achieved when the log dose of a drug
is plotted against the cumulative percentage of a population responding to a
specified drug response. The results of animal experiments can be plotted in this
manner to discern the median effective dose (ED50), median toxic dose (TD50),
and median lethal dose (LD50). The therapeutic index is defined as the ratio of
the TD50 to the ED50. Because it is unethical to design experiments using a full
range of drug doses to determine these indices in humans, the range of
therapeutic drug concentrations and the margin of safety are estimated more
broadly through extrapolation from animal studies, human drug trials, and
clinical experience. In practice, both the risks and benefits of prescribing a
medication are taken into account when making therapeutic decisions. Judgment
about the clinically acceptable risk of toxicity often is influenced by the severity
of the disease being treated.
Figure 8-4 Dose–response curves of some opioids. Fentanyl
has a lower EC50 than morphine and is more potent than
morphine. Both fentanyl and morphine have a higher Emax
than codeine and are more efficacious than codeine.
Meperidine is less potent than morphine but more efficacious
than codeine.
Receptors
The concept of the receptor dates to the turn of the 20th century. Paul Ehrlich
introduced the term receptor as he described sites on what he believed to be a
single very large molecule of cell protoplasm to which bacterial toxins (and later,
drugs) bound to bring about changes in cellular metabolism. John Newport
Langley investigated the actions of curare and nicotine on skeletal muscle and
put forth the concept that drugs bind to specific binding sites or “receptive
substance” to cause their effects. Alfred Joseph Clark then used a simple
mathematical model to quantify the relationship between drug concentration and
response. These discoveries laid the foundation for experimental pharmacology
(44).
Originally, the term receptor was applied generically to all drug targets
because there was no clear sense of how binding gave rise to a biological effect.
This chapter focuses on the principles of pharmacology pertinent to psychoactive
drugs. In this context, the term receptor will be used to designate controllers of
regulatory processes, including transducers for neurotransmitters and hormones
that produce endogenous biological signals.
Receptor Physiology
Receptors contain at least two functional domains: a ligand-binding site and an
effector or message propagation (ie, signaling) area. Receptors can be grouped
according to four common types. These are (i) ligand-gated ion channels, (ii) G
protein–coupled receptor signaling, (iii) receptors with intrinsic enzymatic
activity (guanylate cyclase, serine/threonine kinase, tyrosine kinase activity,
tyrosine phosphatases), and (iv) receptors regulating nuclear transcription. The
relatively small number of mechanisms for cell signaling is fundamental to how
target cells integrate signals from multiple receptors to produce sequential,
additive, synergistic, or inhibitory responses. See Figure 8-5 for types of
receptor–effector linkages.
Figure 8-5 Types of receptor–effector linkage. (From Rang
HP, Dale MM, Ritter JM, et al., eds. Pharmacology. 5th ed.
Philadelphia, PA: Churchill Livingstone, 2003.)
Ligand-Gated Ion Channels

These receptors selectively gate the flow of ions through channels into the cell.
Each unit of these multisubunit proteins spans the plasma membrane several
times. The association of the subunits allows the formation of a wall or pore.
Binding to single or multiple subunits then enables these subunits to rapidly and
cooperatively control channel opening and closing. Excitatory neurotransmitters
(eg, acetylcholine and glutamate) result in a net inward current of cations such as
Na+, Ca+2, and K+, which depolarize the cell and increase the generation of
action potentials. In contrast, inhibitory neurotransmitters (eg, GABA and
glycine) result in the net inward flux of anions, such as Cl−, which hyperpolarize
the cell and decrease the generation of action potentials.
Ligand-gated channels enable rapid transformation of information across
synapses. They are involved in synaptic plasticity required for learning and
memory. The overall function of ligand-gated ion channels can be regulated by
multiple mechanisms, including endocytosis and phosphorylation.
G Proteins and Second Messengers

“Serpentine” receptors coupled to G proteins have an extracellular amino (N)
terminal and an intracellular carboxyl (C) terminal and commonly transverse the
plasma membrane seven times. When agonists approach G protein receptors
from the extracellular fluid, they bind to a site surrounded by the transmembrane
regions. A change of confirmation occurs that is transmitted to the cytoplasmic
loops of the receptor that in turn activates the appropriate intracellular G protein.
Several serpentine receptors exist as dimers or larger complexes. Dimerization
may influence ligand preference and/or regulate the affinity and specificity of the
complex for G protein and for other events important in the termination of action
of the receptor (45). Examples of G protein receptors include muscarinic
acetylcholine receptors, receptors for adrenergic amines, most serotonin
receptors, and many peptide hormone receptors.
G proteins modify the activity of regulatory proteins and/or ion channels,
which in turn alter the activity of intracellular second messengers that enable
signal transduction and amplification. Cells of different tissues may have
different G protein–dependent responses to the same initial ligand (eg,
norepinephrine, acetylcholine, serotonin).
Among the well-established second messenger systems are cyclic adenosine
monophosphate (cAMP) (by means of Gs and Gi), cyclic guanosine
monophosphate (cGMP), and phosphoinositides (by means of Gq). β-Adrenergic
amines, glucagon, histamine, serotonin, and numerous other hormones act on Gs
to increase adenylyl cyclase and then increase the second messenger, cAMP,
whereas 2-adrenergic amines, muscarinic acetylcholine, opioids, serotonin, and
others act on Gi1, Gi2, and Gi3 to decrease adenylyl cyclase and then decrease
cAMP. cAMP stimulates distinct cAMP-dependent protein kinases that are
differentially expressed in varying tissues. When cAMP binds to the regulatory
dimer (D) of the kinase, two catalytic (C) chains are released, which diffuse
through the cytoplasm and nucleus, transferring phosphate from ATP to other
specific enzymes and substrate proteins. When the hormonal stimulation stops, a
diverse group of specific and nonspecific phosphatases quickly reverse the
cAMP-induced phosphorylation of enzyme substrates, and cAMP is degraded to
5′AMP by several cyclic nucleotide phosphodiesterases. The cGMP-based signal
transduction mechanism closely parallels the cAMP-mediated signaling
mechanism, but its presence is limited to a few tissues including intestinal
mucosa and vascular smooth muscle. Whereas methylxanthines (eg, caffeine and
theophylline) act by competitively inhibiting cAMP degradation, sildenafil
produces vasodilation by inhibiting specific phosphodiesterases, which inhibits
cGMP degradation.
Receptors for Gq including muscarinic acetylcholine, bombesin, serotonin
(5-HT1c), and others act through G proteins or tyrosine kinases to stimulate
phospholipase C in the cell membrane that splits phosphatidylinositol-4,5-
bisphosphate (PIP2) into two second messengers, diacylglycerol (DAG) and
inositol-1,4,5-triphosphate (IPc or InsP3). Confined to the membrane,
diacylglycerol activates a phospholipid- and calcium-sensitive protein kinase C,
whereas water-soluble IP3 diffuses through the cytoplasm, enabling the release
of Ca+2 from internal storage vesicles. Elevated cytoplasmic Ca+2 is bound to
calmodulin, which regulates the activities of other enzymes, including calcium-
dependent protein kinases. This signaling pathway is inactivated when IP3 is
dephosphorylated, and DAG is either phosphorylated to phosphatidic acid and
converted back into phospholipids or deacylated to arachidonic acid, and Ca+2 is
actively removed by calcium pumps from the cytoplasm. The phosphoinositide
signaling pathway is more complex than the cAMP pathway, owing to multiple
second messengers and protein kinases. For instance, more than nine structurally
distinct types of protein kinase C have been identified. In addition, protein
kinases of different cell types may have general or specified substrate targets.
Desensitization is a Process whereby Response to a Drug is

Decreased
Desensitization occurs when following an initial response, the response
produced by the agonist diminishes over seconds to minutes despite the
continued presence of agonist. The rapid changes of desensitization can be
contrasted to the slower and more gradual changes of tolerance, where the
diminution of response occurs over days or weeks.
Mechanisms leading to receptor desensitization include (a) conformational
change in the receptor (as occurs with ionic receptors), (b) loss of receptor due to
internalization, (c) depletion of essential mediators, (d) increased metabolic
degradation of drugs, and (e) homeostatic mechanisms that nullify drug effect
(46).
Desensitization may be homologous or heterologous. Homologous
desensitization indicates feedback directed to the receptor molecule itself,
whereas heterologous desensitization (also known as cross desensitization)
extends to the action of all receptors that share a common signaling pathway.
Heterologous desensitization may involve inhibition of one or more downstream
proteins that participate in signaling from other receptors as well. For instance,
desensitization of some G protein–coupled receptors has been shown to involve
phosphorylation of specific residues by G protein receptor kinases (homologous
desensitization) or PKA (heterologous desensitization) enzymes.
G Protein Receptors Undergo Pharmacodynamic Tolerance

When agonists induce conformational change of G protein receptors, the
receptor binds and activates a family of G protein–coupled receptor kinases
(GRKs). The activated GRK then phosphorylates serine residues in the
receptor’s carboxy terminal tail, increasing the affinity for β-arrestin, which in
turn diminishes the receptor’s ability to interact with GS, reducing the
stimulation of adenylyl cyclase and the agonist response. Cellular phosphatases
can terminate GRK activation, facilitate removal of phosphate, and restore initial
responsiveness to the agonist.
Agonists can also induce endocytosis and membrane trafficking of receptors.
β-Arrestin accelerates endocytosis of receptors from the plasma membrane by
binding to endocytotic structures in the plasma membrane called coated pits.
This endocytosis can either result in the receptor’s recycling through the plasma
membrane with continued cellular responsiveness or cause receptor trafficking to
lysosomes such that degradation of the receptor causes down-regulation and
attenuated cellular responsiveness. Recent work by Kim et al. (47) showed that
increased endocytosis and recycling of opioid receptors in the plasma membrane
(created by a knock-in mouse expressing mutant MOP-R) was associated with
continued morphine analgesia but reduced tolerance and physical dependence.
Receptors with Intrinsic Enzyme Activity

These polypeptide receptors typically consist of an extracellular growth factor or
hormone-binding domain connected to a cytoplasmic enzyme domain by a
hydrophobic segment that crosses the plasma membrane’s lipid bilayer. The
cytoplasmic enzyme domain may be a tyrosine kinase, a serine/threonine kinase,
or a guanylate cyclase that, when activated, catalyzes the activity of substrate
proteins followed by additional downstream signaling proteins. For instance,
when epidermal growth factor binds to its receptor, it converts the receptor from
its inactive monomeric state to an active dimeric state of two noncovalently
bound receptor polypeptides. The enzymatic cytoplasmic domains become
activated and catalyze the phosphorylation of substrate proteins. Drugs may
target the agonist binding site and/or the enzymatic activity of the receptor.
Receptors Regulating Nuclear Transcription

Receptors that regulate nuclear transcription are soluble DNA-binding proteins
that bypass the plasma membrane to reach their intracellular targets. They
include (a) the steroid family of androgen, progesterone, glucocorticoid, and
mineralocorticoid receptors; (b) the thyroid/retinoid family consisting of thyroid
hormone, vitamin D, and retinoic acid; and (c) the orphan receptor family, whose
endogenous ligand, if any, remains unknown.
When inactive, these receptors are bound to proteins in the cytoplasm. They
are then assembled as homodimers or heterodimers with ligand-binding, DNA-
binding, and transcriptional regulation domains. The ligand-binding site confers
a negative regulatory role. When hormone binds to the receptor, it relieves an
inhibitory constraint, allowing the DNA-binding domain to bind to specific DNA
sequences (called response elements) on the genome to activate or inhibit
transcription of the nearby gene. For example, when cortisol binds to the
glucocorticoid receptor, heat shock protein 90 is released. This allows the DNA-
binding and transcription-activating domains of the receptor to fold into their
functionally active conformations so that the activated receptor can initiate
transcription of target genes. These hormone-mediated gene actions require time
for synthesis of new proteins and so have a relatively slower onset and offset of
action.
A Mechanistic Classification of Selected Drugs with

Addiction Liability
Addictive substances generally activate the mesolimbic system by (a) interacting
with ion channel receptors, (b) binding to Gio-coupled receptors, or (c)
interfering with monoamine transporters. Substances acting through the first two
mechanisms tend to inhibit GABA inhibitory interneurons, resulting in a net
release of dopamine. Drugs acting indirectly or directly upon ion channel
receptors can additionally increase dopamine in the nucleus accumbens and
ventral tegmental areas. Drugs that interfere with monoamine transporters block
the reuptake or stimulate nonvesicular release of dopamine (41), causing an
accumulation of dopamine in target structures (Table 8-1).
TABLE 8-1 The Mechanistic Classification of Drugs

Involved in Substance Use Disorders
5-HTxR, serotonin receptor; CB1R, cannabinoid-1; DAT, dopamine transporter; GABA, gamma-
aminobutyric acid; Kir3 channels, G protein–coupled inwardly rectifying potassium channels; LSD,
lysergic acid diethylamide; -OR, -opioid receptor; nAChR, nicotinic acetylcholine receptor; NET,
norepinephrine transporter; NMDAR, N-methyl-D-aspartate receptor; SERT, serotonin transporter; VMAT,
vesicular monoamine transporter; ?, data not available.
Reprinted from Katzung BG. Basic and Clinical Pharmacology. 10th ed. New York, NY: McGraw-Hill
Companies, Inc., 2007, with permission.
Nicotine, benzodiazepines, phencyclidine, and ketamine work through

ionotropic receptors. Nicotine activates the nicotinic acetylcholine receptor, and
benzodiazepines are modulators of the GABAA receptor. Alcohol alters the
function of several ionic receptors including GABAA receptors, K+ inwardly
rectifying or G protein–activated inwardly rectifying K+ channels (Kir3/GIRK),
glycine receptors, N-methyl-D-aspartate (NMDA) receptors, and 5-HT3
receptors. Alcohol also inhibits ENT1, the equilibrative nucleoside transporter
for adenosine reuptake, resulting in adenosine accumulation, stimulation of
adenosine A2 receptors, and enhanced cAMP response element–binding (CREB)
protein signaling. Neither phencyclidine nor ketamine is physically addictive or
associated with a physical withdrawal syndrome, but both may lead to a long-
lasting psychosis owing to noncompetitive antagonism of the NMDA receptor.
Of the inhalants, nitric oxide acts on NMDA receptors, whereas fuel additives
enhance GABAA receptor function.
The opioids, cannabinoids, gamma-hydroxybutyric acid, and the
hallucinogens all exert their action through Gio. Even though the mu, kappa, and
delta opioid receptors all inhibit adenylyl cyclase, their selective neuronal
expression results in different effects. For example, mu opioid agonists inhibit
GABA inhibition of dopamine, causing a net release of mesolimbic dopamine,
reinforcement, and euphoria. In contrast, kappa agonists inhibit dopamine
neurons and induce a variety of effects including dysphoria, hallucinations, and
dissociation.
Cannabinoids cause presynaptic inhibition. The lipid-soluble
neurotransmitters 2-arachidonyl glycerol and anandamide bind to cannabinoid
receptor type 1 (CB1 receptor) to induce retrograde signaling from post- to
presynaptic neurons, where they may inhibit the release of either glutamate or
GABA.
The hallucinogens LSD, mescaline, and psilocybin do not cause compulsive
repetitive use and do not directly release dopamine. These drugs act through
many G coupled receptors, including most serotonin, adrenergic, and dopamine
receptors, including D2 receptors. Hallucinogens act in part by enhancing
excitatory afferent input from the thalamus and increasing glutamate release in
the cortex.
Cocaine, amphetamine, methamphetamine, and ecstasy bind to transporters
of biogenic amines. Cocaine inhibits norepinephrine, dopamine, and serotonin
transporters. Its activity is in part due to the decreasing dopamine clearance from
the synaptic cleft and resultant increase in extracellular dopamine. Amphetamine
competitively inhibits dopamine transport at the dopamine transporter and
interferes with the vesicular monoamine transporter to lessen the storage of
dopamine in the synaptic vesicles. As cytoplasmic dopamine increases, there is
reversal of the dopamine transporter, increasing nonvesicular release of
dopamine and further increasing extracellular dopamine. Ecstasy or MDMA,
like amphetamines, causes release of biogenic amines by reversing the serotonin
and other transporters.
Allosteric Modulation of G Protein–Coupled Receptors: Activity

Based upon the Conformational State
It is now believed that G protein–coupled receptors can exist in multiple
conformational states including ones that are active, inactive, partially active,
and selectively active and those that produce nonproductive signaling though
GTP-binding sites. If the conformational states of a receptor are in equilibrium
and the inactive state predominates in the absence of drug, then the basal signal
output from the downstream effector will be minimal or absent.
Drugs can bind to receptors at the same site or at a different site than the
endogenous compound that physiologically activates that receptor. The relative
affinity of the drug for various conformations of the receptor will determine the
extent to which the equilibrium is shifted toward the active state. Full agonists
have a higher affinity for the active conformation and drive the equilibrium
toward the active state. Partial agonists bind to the receptor with only
moderately more affinity for the active than for the inactive receptor. Even at
saturating concentrations, partial agonists will not enable a full biological
response (see Fig. 8-3).
Buprenorphine is an example of a highly potent mu opioid receptor partial
agonist. The drug has a high affinity for mu receptors and displaces morphine,
methadone, and other full opioid agonists from these receptors. In contrast to the
full agonists, however, increases in buprenorphine dose may result in a longer
duration of action but do not result in increased pharmacological effects. Higher
doses of buprenorphine can be given without respiratory depression. The partial
agonist properties of buprenorphine may precipitate withdrawal in individuals
who have a high level of physical dependence on opioids.
Antagonists have no effect upon response when used alone. They bind with
equal affinity to the active and inactive conformations and prevent an agonist
from inducing a response (48). Competitive antagonists may be reversed by
adding excess agonist, but noncompetitive antagonists cannot be counteracted in
this manner. With noncompetitive antagonists, there is a decrease in the agonist-
induced Emax (maximal efficiency). The potency of some antagonists,
particularly those that act by inhibiting the activity of an enzyme, often are
expressed as an I50 value, which is the concentration of antagonist needed to
elicit a 50% inhibition of enzyme activity.
Inverse agonists have preferential affinity for inactive receptor
conformations when otherwise the equilibrium would be shifted toward an active
receptor. In this case, inverse agonists produce an effect opposite to those of an
agonist. However, if the basal equilibrium lies in the direction of the inactive
receptor, then there will be little change in activity, and it will be difficult to
distinguish inverse agonism from simple competitive antagonism (49).
Receptors can be constitutively in an active conformation, or they can be
activated by physiological events even in the absence of an agonist.
Pharmacological agents that can induce or stabilize specific receptor
conformations may be therapeutic. Inverse agonist drugs may be clinically
useful if they can selectively prevent the pathological aspects of receptor
activation (49).
Agents that work at GABA-gated chloride ion channels illustrate this
spectrum of drug activity. The endogenous agonist GABA acts at this receptor to
produce inhibitory, hyperpolarizing postsynaptic potentials. Depending on
variations in receptor structure and location in the central nervous system, this
activity produces an assortment of sedative, anxiolytic, and anticonvulsant
effects. Both barbiturates and benzodiazepines are pharmaceutical agonists that
act at the GABA receptor. Binding of each of these drugs to the GABA receptor
complex occurs at distinct sites and facilitates the activity of GABA to open the
chloride ion channel. Benzodiazepines increase the frequency of GABA-
mediated chloride ion channel opening, whereas barbiturates increase the
duration of this opening (50). Bicuculline, a competitive antagonist of GABA,
binds selectively to the GABA site, interfering with GABA binding to that site.
In contrast, picrotoxin, a noncompetitive antagonist of GABA, binds to the
barbiturate site on the receptor, blocking the channel directly. Beta-carboline is
an inverse agonist that reduces chloride ion conductance and increases
excitability and irritability of the central nervous system; in fact, beta-carboline
has no therapeutic use and can precipitate panic attacks. Flumazenil is an
antagonist. Flumazenil lacks intrinsic activity but has therapeutic utility in
treating benzodiazepine overdose. Flumazenil also blocks beta-carboline activity,
although it does not antagonize the actions of ethanol or barbiturates.
Some drugs, depending on their concentrations, act as mixed agonists and
antagonists. Mixed opioid agonist–antagonists have been developed in an
attempt to produce analgesia with drugs that have less addictive potential and
less respiratory depression. For example, nalbuphine and butorphanol are
competitive mu receptor antagonists that exert their analgesic actions by acting
as agonists at kappa receptors. Although each of these drugs has a place in the
therapeutic armamentarium, unfortunately, each can be addiction producing and
associated with adverse effects, especially at higher doses.
Tolerance, Sensitization, and Physical Dependence

Tolerance and sensitization reflect changes in the way the body responds to a
drug when it is used repeatedly. Tolerance is the reduction in response to a drug
after its repeated administration. Tolerance shifts the dose–response curve to the
right, requiring higher doses than the initial doses to achieve the same effect.
Sensitization indicates an increase in drug response after its repeated
administration. Sensitization shifts the dose–response curve to the left, so that
repeated doses cause a greater effect than that seen with the initial dose.
Tolerance and sensitization develop more readily to some drug effects than
to other effects of the same drug. For example, tolerance to the euphoria
produced by cocaine occurs much more rapidly than does tolerance to its
cardiovascular effects. The discrepancy between tolerance to the “rush”
experienced by persons with a substance use disorder and tolerance to a drug’s
cardiovascular and respiratory effects can be an important cause of mortality in
the person with a substance use disorder who overdoses. Also, people who
chronically use opioids often have constipation and constricted pupils even
though they no longer feel “high” after taking their drug (51). Differential
toxicity can be explained by the dissimilar rates of drug tolerance that occur in
diverse organ systems in individuals with unlike host characteristics.
Rodents experience sensitization, evidenced by an increase in locomotion,
after being exposed to intermittent repeated doses of cocaine or amphetamine. In
one study (52), this increase in behavioral activity was linked to an increase in
dopamine levels in the extracellular fluid of the nucleus accumbens. Rats given
repeated daily intraperitoneal cocaine injections (10 mg/kg) for 7 days had
higher levels of dopamine detected by microdialysis on the 7th day than on the
first day. Sensitization can be a phenomenon underlying chronic stimulant
psychosis and/or alcohol withdrawal seizures.
There are several mechanisms by which tolerance can occur.
Pharmacokinetic tolerance most often occurs as a consequence of increased
metabolism of a drug after its repeated administration, resulting in less drug
being available at the receptor for drug activity. For example, the microsomal
ethanol-metabolizing system, which usually is not important in metabolizing
ethanol, can be induced by prolonged ethanol exposure. Pharmacodynamic
tolerance refers to the adaptive changes in receptor density, efficiency of
receptor coupling, and/or signal transduction pathways that occur after repeated
drug exposure. Homologous and heterologous desensitization were discussed
earlier under G protein receptors. Additional discussion about the mechanisms
for pharmacological tolerance is discussed in the chapters that follow.
Learned tolerance refers to a reduction in the effects of a drug because of
compensatory mechanisms that are learned. A common example of learned
tolerance is the ability for roofers and workers at heights to walk in a straight
line despite motor impairment from alcohol intoxication. Conditioned tolerance,
which is a subset of learned tolerance, occurs when specific environmental cues
such as sights, smells, or circumstances are paired with drug administration so
that, when the drug is taken in the presence of the specific environmental cue, a
state of expectation occurs. With expectation, the drug effect may be experienced
before the drug is taken—and an adaptive response may be learned (53). A
powerful example of conditioned tolerance occurred in a study when rats died
after being given a dose of opioids to which they previously had been tolerant.
The deaths occurred when the rats were put in an unusual environment instead of
the home cage where they were used to receiving the drug (54).
Cross-tolerance occurs when tolerance to the repeated use of a specific drug
in a given category is generalized to other drugs in that same structural and
mechanistic category. The cross-tolerance that occurs between alcohol,
barbiturates, and benzodiazepines can be used to facilitate the smooth weaning
of a patient from their drug of addiction during withdrawal management (see
Section 6, “Management of Intoxication and Withdrawal”).
Physical dependence is a state that develops as a result of the adaptation
produced by resetting homeostatic mechanisms after repeated drug use and may
require medical monitoring during the initial absence of the drug, especially in a
patient who has significant comorbidities. Physical dependence can manifest
itself in the appearance of both physical and psychological symptoms that are
caused by physiological adaptations in the central nervous system and the brain
due to chronic exposure to a substance. For example, the Clinical Opioid
Withdrawal Scale measures increased pulse, sweating, restlessness, pupillary
dilatation, bone and joint aches, rhinorrhea and lacrimation, GI upset, tremor,
yawning, anxiety or irritability, and piloerection. Drug withdrawal is one of the
DSM 5 criteria for substance use disorder, but it is neither necessary nor on its
own or sufficient for making this diagnosis.
Drugs such as ethanol and opioids produce withdrawal syndromes that may
include increased heart rate and/or blood pressure, sweating, and tremors; more
serious withdrawal symptoms such as hallucinations; and medical emergencies
such as seizures. Withdrawal signs and symptoms can occur in a physically
dependent person when drug administration is abruptly stopped. Withdrawal
symptoms may reflect the interactions of numerous neurocircuits and organ
systems. The molecular mechanisms of physical dependence caused by
individual drugs are discussed in the chapters that follow.
Patients who take prescribed medications for appropriate medical indications
can show tolerance, physical dependence, and withdrawal if the drug is stopped
abruptly, even though they do not exhibit the compulsive drug use and negative
consequences characteristic of a substance use disorder or addiction. The
hypertensive rebound that occurs in patients when chronic administration of
beta-adrenergic receptor blockers is abruptly discontinued is but one example of
this phenomenon. Similarly, patients with chronic pain may develop tolerance to
the pain relieving properties of opioids. They may also develop physical
withdrawal if chronically administered opioids are abruptly discontinued. Pain
patients will not fulfill the diagnostic criteria for opioid use disorder by merely
being tolerant and/or physically dependent upon this medication (see Section 12,
“Pain and Addiction”).
Fetal Pharmacokinetics and Abstinence

With the recent epidemic of opioid overdose and opioid use disorder, there is a
dramatic increase in the number of infants born to opioid-addicted mothers.
Since the fetus receives nutrients and other substances via the placenta, the fetus
is likewise exposed to opioids. The placenta is similar to the blood–brain barrier
in many respects, including transport mechanisms. Most transport from the
maternal to fetal circulation occurs passively, where protein binding, molecular
weight, ionization, and lipophilicity affect transport. The placenta also has
transporters, including the efflux transporter P-glycoprotein (Pgp), whose
activity changes/increases with gestational age. The placenta also has the ability
to metabolize compounds much like the liver (55,56).
Lipid soluble opioids readily pass through the placenta to the fetus. Fentanyl
is more lipophilic than morphine and so passes more readily. Nicotine is also
transferred. At birth, the frequent combination of addictive substances such as
nicotine, alcohol, and benzodiazepines in the opioid-addicted mother creates a
complex withdrawal picture in the neonate.
SUMMARY
This chapter gives an introduction to the pharmacological principles that
underlie the use of drugs for both therapeutic and nontherapeutic purposes.
Topics included pharmacokinetics, the study of the time course of drug
concentrations as determined by absorption, distribution, metabolism,
elimination, and excretion; pharmacodynamics, the study of the biochemical and
physiological effects of drugs and their mechanisms of action; and
pharmacogenomics, the relationship between individual genetic polymorphisms
and drug disposition and effect. An introduction to receptor physiology of
ligand-gated ion channels, G proteins and second messengers, receptors with
intrinsic enzyme activity, and receptors regulating nuclear transcription built the
foundation for discussing a mechanistic classification of selected substances
(41). Next, new concepts of allosteric modulation of G protein–coupled
receptors formed the backdrop for a discussion of full and partial agonists as
well as competitive and noncompetitive antagonists. The following chapters in
this section elaborate on the pharmacology of individual drugs that contribute to
substance use disorders, including further information about the topics of
tolerance, sensitization, and physical dependence.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to Elinore McCance-Katz, MD,
whose contributions to the pharmacogenomics portion of previous versions of
this chapter set the stage for this sixth edition.
The conclusions in this chapter represent the views of the authors and do not
necessarily represent the views of the Office of Clinical Research of the National
Institute of Health.
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CHAPTER 9
The Pharmacology of Alcohol
John J. Woodward
CHAPTER OUTLINE
Definition
Substances Included in This Class
Formulations and Methods of Use
Clinical Uses
Brief Historical Features
Epidemiology
Pharmacokinetics
Pharmacodynamics
Drug–Drug Interactions
Neurobiology (Mechanisms of Addiction)
Addiction Liability
Conclusions/Future Research
DEFINITION
Alcohol is a chemical name for a group of related compounds that contain a
hydroxyl group (–OH) bound to a carbon atom. The form of alcohol that is
voluntarily consumed by humans is ethyl alcohol or ethanol and consists of two
carbons and a single hydroxyl group (written as C2H5OH or C2H6O). Unless
otherwise noted, the term alcohol will be used throughout this chapter to mean
ethanol.
SUBSTANCES INCLUDED IN THIS

CLASS
In terms of human consumption, all commercially available alcoholic beverages
contain ethyl alcohol with concentrations depending upon the type of beverage.
Beverages made by fermentation of sugar-containing fruits and grains include
beer (3%-8% ethanol by volume) and wines (11%-13% ethanol by volume).
Spirits are produced after distillation and generally contain at least 30% ethanol.
Ethanol can be concentrated by simple distillation up to ~95%, while pure
ethanol requires addition of benzene or related substances or desiccation using
glycerol. Denatured alcohol contains additives or toxins to prevent human
consumption. Rubbing alcohol is prepared from denatured alcohol or isopropyl
alcohol and is used for topical purposes.
FORMULATIONS AND METHODS OF

USE
A bewildering array of alcoholic beverages is available for consumption, and
these products contain a wide range of alcohol concentrations. In the United
States, a standard alcoholic drink is defined as one that contains 0.6 fluid ounces
of alcohol. Thus, this amount of alcohol is typically contained in 12 oz of beer, 5
oz of wine, or 1.5 oz of distilled spirits (40% ethanol by volume) although this
can vary depending on the specific type of beverage (Table 9-1). Although most
alcohol is consumed orally, there are isolated cases of individuals injecting
ethanol intravenously (1) and other means of administration are also used. For
example, ethanol vapor is often used to induce physical dependence in rodent
models of alcoholism (2,3), and machines called AWOL (alcohol without liquid)
have been marketed as a novel means of self-administering alcohol. A number of
US states have since banned the sale or use of these devices. Ethanol vapor may
also be inhaled through the use of e-cigarettes that often contain ethanol as part
of the manufacturing process or following user adulteration (4). The impact of
this route of administration is not yet fully known but could contribute to higher
blood alcohol levels when combined with drinking. In addition to the
inhalational route, several forms of powdered alcohol have been developed (eg,
Palcohol) that involves microencapsulation with a water soluble carrier such as
maltodextrin. Although initially approved for use in the United States in 2015, a
variety of US states have introduced legislation to ban powdered alcohol due to
perceived concerns over its safety particularly with regard to unauthorized use
by children and adolescents.
TABLE 9-1 Amount of Alcohol in Different Beverages

and Relationship to a Standard Drink
In the United States, a “standard drink” is one that contains ~0.6 fluid ounces (14 g) of pure alcohol.
CLINICAL USES
In addition to its use as a topical antiseptic, alcohol has several clinical
indications including treatment of accidental or voluntary ingestion of methanol
or ethylene glycol (5). Ethanol has a higher affinity for alcohol dehydrogenase
(ADH) than methanol and thus reduces the formation of methanol metabolites
formaldehyde and formic acid. For both indications, hemodialysis is the
recommended first line of treatment. Alcohol has also been used for treatment of
various types of cysts (sclerotherapy) and was used historically for treatment of
premature labor (5). Safer and more effective medications have largely replaced
these uses. Alcohol combined with dextrose is used to increase caloric intake
and for replenishing fluids. Alcohol, either given orally or IV, is sometimes used
by physicians to treat withdrawal, particularly in a hospital setting. For example,
a survey of in-patient hospital pharmacies reported that approximately one-half
had alcohol available for treatment of withdrawal with surgical services
requesting the majority of these uses (6).
BRIEF HISTORICAL FEATURES

Alcohol is one of the oldest used substances. Consumption of alcohol-containing
beverages predate recorded human history, while written records of its use are
found in Chinese and Middle Eastern texts as far back as 9000 years ago.
Alcoholic beverages have long been consumed as part of the daily diet and are
also used for medicinal or symbolic effects. In modern times, alcohol is second
only to caffeine in incidence of use, and its manufacture, distribution, and sale
are of major economic importance across the world. Alcohol use worldwide is
regulated by both societal and religious beliefs. In the United States,
consumption of alcohol was legally restricted on the national level with passage
of the Volstead Act and the Eighteenth Amendment to the US Constitution in
1919 (7). Amid growing public outcry, prohibition was repealed in 1933 with the
ratification of the Twenty-first Amendment that gave states the right to regulate
the purchase and sale of alcohol. Today, sales and consumption of alcohol are
under control of a wide variety of local and state laws.
EPIDEMIOLOGY
The lifetime exposure to alcohol is high with nearly 88% of the US population
reporting using alcohol at least once in their lifetime (8). In 2013, current alcohol
use (defined as use in the past 30 days) of Americans ranged from 2.1% among
12- to 13-year-olds to nearly 70% of 21- to 25-year-olds. Prevalence decreased
among older groups although it was nearly 54% among 60- to 64-year-olds (8).
Rates of binge drinking (five or more drinks within a few hours) for persons 12
and older approached 23% in 2013 while heavy drinking (five or more drinks on
each of 5 or more days in the past 30) was reported by 6.3% of the US
population. The latest estimate of annual alcohol-related costs (2010) in terms of
lost productivity and healthcare was $249 billion (9).
Clinical studies of alcohol use have led to the idea that there may be several
types of alcohol use disorders, based on the appearance and severity of certain
alcohol-related problems (10). Two particularly well-known examples of these
classifications are the type I and II forms proposed by Cloninger and colleagues
and the type A and B forms proposed by Babor (11). Cloninger’s type I and
Babor’s type A share several similarities including (a) later onset of alcohol-
related problems (>25 years old); (b) fewer childhood behavior problems; (c)
relatively mild alcohol-related issues with fewer hospitalizations; and (d) lower
degree of novelty seeking coupled with a preference toward harm avoidance.
Type II and B forms show essentially the opposite characteristics as type I/A and
include (a) familial alcoholism, (b) earlier onset of alcohol-related problems, (c)
more incidents of alcohol-related problems or violence, and (d) higher
preference for risk-taking/novelty seeking.
PHARMACOKINETICS
Absorption and Metabolism

Alcohol is a small, water soluble molecule that is rapidly and efficiently
absorbed into the bloodstream from the stomach, small intestine, and colon. The
rate of absorption depends on the gastric emptying time and can be delayed by
the presence of food in the small intestine. Once in the bloodstream, alcohol is
rapidly distributed throughout the body and gains access to all tissues, including
the fetus in pregnant women. Although the relationship between alcohol intake
and blood levels is body weight dependent, gender is also important. When body
weights are equivalent, women show a 20%-25% higher blood alcohol level than
men following ingestion of the same amount of alcohol (Table 9-2). This appears
to be due primarily to less gastric metabolism of alcohol in women as blood
levels are not significantly different when alcohol is administered intravenously
(12).
TABLE 9-2 Estimated Blood Alcohol Levels Following

Drinking
Data represent blood alcohol concentration (gram per 100 mL or gram %) for men (M) and women (F)
following consumption of different number of drinks. Subtract 0.01 from each value for each hour of
drinking to account for effects of metabolism. One drink represents 12 oz beer, 5 oz wine, or 1.5 oz liquor.
Alcohol is metabolized primarily by enzymatic pathways and only small

amounts of alcohol are excreted through the lungs as vapor. The odor of the
breath is not a reliable indicator of alcohol consumption because it is influenced
by impurities in the alcoholic beverage. In the liver, alcohol is broken down by
ADH and mixed function oxidases such as P450IIE1 (CYP2E1). Levels of
CYP2E1 may be increased in chronic drinkers. ADH converts alcohol to
acetaldehyde, which subsequently can be converted to acetate by the actions of
acetaldehyde dehydrogenase (ALDH).
The rate of alcohol metabolism by ADH is relatively constant, as the enzyme
is saturated at relatively low blood alcohol levels and thus exhibits zero order
kinetics (constant amount oxidized per unit of time). Alcohol metabolism is
proportional to body weight (and probably liver weight) and averages ~1 oz of
pure alcohol per 3 hours in adults. Thus, the time for an individual to become
sober after even moderate intake of alcohol can be substantial. Although
stimulants are often used to mask the depressant effects of alcohol, there do not
appear to be any truly effective “alcohol antagonists” (amethystic agents) that
can quickly reverse the intoxicating effects of alcohol. Naloxone (Narcan), the
opioid antagonist, has been tested for its ability to reverse alcohol-induced coma
but appears ineffective (13). Several GABAA receptor antagonists have also
been examined including flumazenil (Anexate) that is used to treat
benzodiazepine overdose and the experimental compound RO 15-4513. This
compound, which is actually an inverse agonist, has been reported to reverse
some of the effects of low to moderate doses of alcohol in animals and may
target a very specific subtype of GABAA receptor that shows sensitivity to very
low concentrations of ethanol (14). In addition to these agents, clinical trials
have shown that metadoxine (pyridoxal L-2-pyrollidone-5-carboxilate) appears
to enhance the metabolic clearance of alcohol and speed recovery of intoxicated
individuals (15). Although the clinical utility of an antialcohol medication for
emergency medicine is undoubtedly high, moral, ethical, and medical concerns
must be considered with respect to the development and general use of such a
drug since it would not be expected to alter the underlying deleterious effects of
alcohol on organ systems.
PHARMACODYNAMICS
Central Nervous System

Acutely, alcohol acts as a central nervous system (CNS) depressant. During the
initial phase when blood alcohol levels are rising, a period of disinhibition often
occurs and signs of behavioral arousal are common. These include relief of
anxiety, increased talkativeness, feelings of confidence and euphoria, and
enhanced assertiveness. As drinking continues, there are impairments in
judgment and reaction time, increased emotional outbursts, and ataxia. At higher
blood levels, alcohol acts as a sedative and hypnotic, although the quality of
sleep often is reduced after alcohol intake. In patients with sleep apnea, alcohol
increases the frequency and severity of apneic episodes and the resulting
hypoxia. Alcohol potentiates the sedative-hypnotic properties of both
benzodiazepines and barbiturates, perhaps reflecting common mechanisms of
action for these substances. Acute alcohol intoxication is not always associated
with sedation or coma; indeed, some intoxicated individuals display violent
behavior that requires administration of other sedative or antipsychotic agents.
The use of these agents with a severely intoxicated individual must be
approached cautiously to prevent respiratory failure. Chronic unhealthy use of
alcohol as with alcohol use disorder can result in Wernicke-Korsakoff syndrome,
which is associated with deficiencies in nutrition and vitamin intake (particularly
thiamine).
Other Organ Systems

An in-depth discussion of the actions of alcohol on various organ systems can be
found in other chapters of this book. A brief review of the most common effects
is given here. Acute alcohol ingestion usually produces a feeling of warmth as
cutaneous blood flow is increased, and this is accompanied by a reduction in
core body temperature. Gastric secretions are usually increased, although the
concentration of alcohol ingested affects this response, with high concentrations
(>20%) inhibiting secretions (16). Long-term ingestion of high concentrations of
alcohol can lead to a variety of pathologies associated with the gastrointestinal
(GI) tract including esophageal varices and bleeding, erosive gastritis, and
diarrhea and malabsorption of nutrients and vitamins (16). Alcohol consumption
is also associated with an increased risk of tumors in the GI system as well as in
other tissues including the lung and breast (17). Acute and chronic ingestion of
alcohol generally decreases sexual performance in both men and women
although sexual behavior may be enhanced due to loss of inhibitory control and
judgment. Alcohol has manifold effects on the cardiovascular system and
changes in contractility and function can follow both acute and chronic ingestion
of alcohol (18). The deleterious effect of alcohol on the heart and other organ
systems is countered by protective effects of small amounts of alcohol on
cardiovascular tissue (19). Thus, low to moderate alcohol use is associated with
a reduced risk of coronary disease, and this may arise from alcohol-induced
changes in plasma lipoproteins and alterations in cell protection pathways.
Chronic alcohol ingestion is well known to increase fat accumulation in the liver
that can progress to liver enzyme elevation, fatty infiltration, and eventually
cirrhosis (20). Alcohol-induced liver damage is due in part to the production of
acetaldehyde that readily reacts with proteins, lipids, and other compounds
leading to impaired mitochondrial function.
DRUG–DRUG INTERACTIONS
Alcohol has depressant actions on the CNS that are similar to other centrally
acting drugs, such as barbiturates, benzodiazepines, general anesthetics and
solvents, and anticonvulsants. Alcohol also enhances the sedative effects of
antihistamines that are commonly used in the treatment of nasal congestion.
Combining these medications with alcohol can result in significant CNS
depression and reduced ability to carry out normal functions safely, such as
automobile driving. Alcohol can also enhance the hepatotoxic effects of
acetaminophen (Tylenol) and the gastric irritating effects of NSAIDs, thus
increasing the risk for development of gastritis and upper GI bleeding. Chronic
alcohol use can slow the metabolism of certain medications due to reduced liver
function.
NEUROBIOLOGY (MECHANISMS OF
ADDICTION)
A widely accepted tenet of addiction research is that addictive substances, by
definition, produce pleasurable effects that engender actions promoting further
drug seeking and taking. This concept suggests that drugs like alcohol must
produce, at least initially, some form of positive reinforcement that provides a
strong incentive to reexperience the drug. As drug use proceeds, the degree of
acute reinforcement or reward may be attenuated, and reasons for drinking may
erode to where the person drinks less for pleasure and more just to relieve
recurrent alcohol withdrawal (21). The repetitive nature of drug use also engages
mechanisms of learning leading to entrained behaviors that may become highly
ritualistic and habit-like. These findings have led to the idea that drug and
alcohol addiction is a form of dysfunctional, maladaptive learning that, once
established, is difficult to reverse (22). In terms of brain systems that underlie the
development of addiction, recent studies suggest an important interaction
between midbrain dopamine-based reward systems and cortical mechanisms of
brain plasticity and learning that are mediated by the neurotransmitter glutamate
(23). As addiction transitions into more habitual and compulsive behaviors and
aversive symptoms appear, brain stress systems such as the extended amygdala
are recruited and modulators such as corticotrophin-releasing factor (CRF) and
dynorphin may gain importance.
All drugs including alcohol affect reward pathways by enhancing the release
of dopamine (DA) from midbrain dopaminergic projections that regulate
neurotransmission within limbic and cortical circuits that regulated motivated
behavior (24). The DA neurons involved in this action reside in the midbrain
ventral tegmental area (VTA) and project to discrete areas of the brain, including
the nucleus accumbens, olfactory tubercle, frontal cortex, amygdala, and the
septal/hippocampal areas. These regions are thought to be involved in translating
emotion and perception into action through the activation of motor pathways;
thus, they may be important in initiating and sustaining drug-seeking behavior.
Lesions or inactivation of these discrete brain areas in experimental animals can
reduce both the acquisition of drug seeking as well as its reinstatement following
long periods of abstinence (25,26).
The initial reinforcing actions of alcohol appear to involve excitation of VTA
dopamine neurons. Acutely, alcohol enhances the firing rate of midbrain DA
neurons and animals will self-administer alcohol directly into the posterior but
not anterior VTA (27,28). Chronic exposure to alcohol leads to alterations in the
excitability of these neurons in the absence of alcohol that may persist for
significant periods of time (29,30). Electrophysiological studies have
demonstrated enhanced efficiency of glutamatergic signaling in neurons
following exposure to alcohol and other drugs (31–33). With respect to reward
circuits, these findings suggest that enhanced firing of VTA DA neurons during
exposure to alcohol facilitates glutamatergic transmission in limbic, cortical, and
striatal areas thus strengthening the association between behavioral action and
outcome. Studies using in vivo microdialysis to monitor levels of dopamine in
freely behaving animals report significant dose-dependent increases in
extracellular dopamine levels in the nucleus accumbens in rats self-
administrating alcohol (34,35). Importantly, in rats genetically selected to
consume large amounts of alcohol, significant increases in dopamine were also
observed during the 15-minute waiting period that preceded alcohol self-
administration (36). This finding suggests that, in animals with drinking
experience, the expected reward that ingestion of alcohol provides is itself
sufficient to enhance activity in this pathway. The subsequent pharmacologically
induced elevation of dopamine that occurs during drinking may further
strengthen the motivation to consume alcohol in future sessions. Genetic
differences in the responsiveness of this pathway may contribute to the
motivational factors that drive greater alcohol-seeking behavior in certain
individuals.
Studies with human subjects with alcohol use disorder have examined the
neurobehavioral aspects of alcohol use, using drug discrimination procedures
similar to those used in animal studies. In these studies, human subjects with
alcohol use disorder are asked to rate the effects produced by a variety of drugs
in terms of their similarity to those produced by alcohol. For example, ketamine,
a dissociative anesthetic that blocks the ethanol-sensitive N-methyl-D-aspartate
(NMDA) subtype of glutamate receptors, induces ethanol-like subjective effects
in recently detoxified people with alcoholism (37). These effects were dose
dependent: at low doses, they mimicked the effects of one to two standard drinks
of alcohol, whereas higher doses produced effects similar to those of eight to
nine drinks. Interestingly, the effects of ketamine that were ethanol-like were
associated with the descending phase of blood alcohol concentration that is
associated with ethanol-induced sedation.
Other human clinical studies using selective pharmacological agents have
implicated neurotransmitters such as γ-aminobutyric acid (GABA), serotonin,
and the opiates in mediating the rewarding and craving aspects of alcohol action.
Results from human imaging studies have begun to identify changes in brain
activation during exposure to alcohol or alcohol-related cues between control
and DSM-defined alcohol-dependent subjects (38,39). Such human studies are
important in the context of understanding the underlying causes of alcohol use
disorder because alcohol, unlike most drugs, interacts with a wide variety of
molecular and cellular processes to produce its pharmacological, physiological,
and psychological effects.
Molecular Sites of Alcohol Action

Psychostimulants such as cocaine and amphetamine or opioids like heroin and
morphine all produce their primary effect by binding to specific protein receptors
expressed on brain neurons. In contrast, alcohol is rather promiscuous and
interacts with a wide variety of targets including both lipids and proteins. Initial
observations made by the German scientists Meyer and Overton over 100 years
ago led to a lipid-disordering hypothesis of alcohol and anesthetic action due to
the high correlation between lipid solubility of a compound and its potency as an
anesthetic. Support for this theory has waned in recent years due to several
factors. For example, measurable changes in membrane fluidity require very
high concentrations of alcohol, are relatively modest, and are less marked than
the effects produced by small changes in temperature that are not associated with
behavioral signs of intoxication (40). These findings and the demonstration of
effects in lipid-free systems have led to the idea that alcohol’s acute actions are
likely due to effects on ion channel proteins that regulate the excitability of
neurons (41). An important point to consider in these in vitro studies of alcohol
action is whether the range of concentrations needed to cause significant effects
are similar to those associated with the behavioral actions of alcohol. Blood
alcohol concentrations in the range 40-400 mg% are equivalent to 8-88 mM and
are associated with the full spectrum of alcohol intoxication (described in more
detail below). Thus, in vitro studies of alcohol’s effect on ion channels are
usually conducted at concentrations below 100 mM in order to better
approximate levels found in the brain during drinking.
Table 9-3 shows a variety of ligand-gated ion and voltage-activated ion
channels that are expressed by neurons and that are sensitive to behaviorally
relevant concentrations of alcohol.
TABLE 9-3 Properties of Alcohol-Sensitive Ion

Channels
Ion channels are listed according to their natural agonist or mode of activation. Subunit families represent
those found in the brain or spinal cord. Brain subtypes are examples of subunit combinations commonly
expressed by neurons (* indicates other subunits likely required). Alcohol effect indicates change in ion
channel function by alcohol acutely administered to recombinant or native receptor preparations.
Alcohol’s acute depressant action on neuronal excitability likely results from its
ability to enhance the function of inhibitory ion channels while blocking the
activity of excitatory receptors (Fig. 9-1).
Figure 9-1 Structure and location of alcohol-sensitive ion
channels in the neuronal synapse.
GABAA and Glycine Receptors

As shown in Table 9-3, there are distinct families of subunits that make up
GABAA and glycine receptors. Each class of subunits may have multiple
members that differ slightly in their sequence and function. Different subunit
combinations give rise to GABAA and glycine receptors that can show variable
sensitivity to pharmacological agents, including alcohol. Alcohol generally
enhances GABAA and glycine receptor function, although GABAA ρ receptors
are inhibited by alcohol. Initial studies with recombinant GABAA receptors
suggested that the γ2L subunit that contains an additional eight amino acids,
including a site for phosphorylation of the receptor by protein kinase C, was
important for alcohol potentiation of channel function (42,43). Despite these
intriguing results, subsequent studies have shown that γ2L expression is not
sufficient in itself to confer sensitivity to alcohol (44). In addition, knockout
mice lacking this subunit show normal sensitivity to alcohol, although their
responsiveness to benzodiazepines is enhanced (45,46). While these results
appear to rule out a major role for the γ2 subunit in mediating alcohol action on
GABAA receptors, this may be phosphorylation dependent as the alcohol
sensitivity of GABAA α1β2γ2 receptors was reported to be markedly enhanced
when the kinase PKCε was inhibited (47). Mice lacking PKCε also show an
enhanced response to ethanol suggesting that specific subtypes of GABAA
receptors may show appreciable alcohol sensitivity under certain conditions (48).
In addition to γ containing GABAA receptors, recent studies suggest that δ
containing GABA receptors possess high sensitivity to relatively low levels of
alcohol. These receptors contain the α4(6), β and the δ subunit instead of the γ
subunit and are affected by concentrations of ethanol (5-10 mM) achieved after
only one drink (49). Despite these intriguing findings, not all studies have
reported that δ containing GABAA receptors are sensitive to low concentrations
of alcohol (50). While the reasons underlying these conflicting findings are not
yet clear, ethanol sensitive GABAA receptors may not be required for mediating
some effects of alcohol. For example, following restraint stress in rats, GABAA
receptors in GABA interneurons in the VTA became depolarizing due to reduced
efficacy of the KCC2 chloride transporter (51). This led to enhanced inhibition
of VTA DA neurons, blunted ethanol-induced increases in nucleus accumbens
DA, and increased drinking in the stressed rats.
Glycine receptors also gate the flux of chloride and serve as important
regulators of neuronal excitability in both spinal cord and brain. Ethanol
enhances currents through glycine receptors, and this enhancement appears
restricted to α1 containing forms (reviewed by Burgos et al. (52)). Ethanol can
also affect excitability via ethanol-insensitive glycine receptors by releasing
glycine from glial sources that then activate neuronal glycine receptors (53,54).
A major approach that has revolutionized the study of alcohol action on ion
channels is the use of site-directed mutagenesis to alter putative alcohol-sensitive
amino acids within a given receptor. These sites are often located within
transmembrane domains of individual receptor subunits and in GABAA or
glycine receptors, replacement of a conserved serine by an isoleucine abolished
the potentiating effects of alcohol on receptor currents (55). Subsequent studies
have shown that this site may also be involved in mediating the effects of some
volatile anesthetics on GABAA and glycine receptor function (56). The
identification of these alcohol-sensitive residues combined with development of
ion channel structural models has allowed for detailed molecular modeling of
these sites and the development of genetically modified animals that express
alcohol insensitive subunits (57).
Interestingly, GABAA and glycine receptor knockout and knock-in mice
appear to show relatively subtle changes that are restricted to specific alcohol-
induced behaviors with little effect on other alcohol actions (58–62). This may
reflect the fact that there are multiple targets for alcohol in the brain and that in
the case of knockout animals, changes in expression of related GABA or glycine
subunits may compensate for the loss of those that are alcohol sensitive (63). In
addition, there is now good evidence that some of the effects of alcohol on
GABA receptor function arise from changes in the presynaptic release of GABA
rather than a direct effect on the GABA receptor itself (64). For example, in
certain neurons of the amygdala, a brain structure highly involved in processing
emotionally relevant stimuli, alcohol’s potentiation of postsynaptic GABAA
responses appears to be due to an increase in the release of GABA rather than a
direct effect on the channel (65). The mechanism underlying the sensitivity of
GABA release to alcohol is not currently known but could involve specific
signaling pathways and proteins that normally regulate vesicle movement and
fusion (66).
Glutamate Activated Ion Channels

Glutamate is the major excitatory neurotransmitter in the brain and activates
three major subtypes of ion channels called AMPA, kainate, and NMDA
receptors. These channels mediate most of the fast excitatory synaptic
transmission in the brain and are critical mediators of most forms of synaptic
plasticity thought to underlie learning and memory. NMDA receptors are highly
calcium permeable and require both glutamate and glycine for activation while
AMPA and kainate receptors only require glutamate for activation. As reviewed
below, NMDA receptors are inhibited by ethanol as well as other substances
including nitrous oxide, anesthetics, and volatile solvents such as toluene
(67–69).
In general, NMDA receptors show appreciable sensitivity to relevant
concentrations of alcohol (70), while AMPA and kainate receptors show a more
restricted pattern of ethanol sensitivity (53,71,72). NMDA receptors expressed in
most neurons are readily antagonized by alcohol at concentrations (10-100 mM)
associated with intoxication and sedation although this varies across different
brain regions (53,72–76). Like GABAA and glycine receptors, alcohol inhibition
of NMDA receptors may involve an interaction with specific residues within
defined transmembrane domains of the receptor that control channel gating
(77–79). NMDA responses show regional and developmental variation in their
sensitivity to alcohol, and this variation may result from differential expression
of GluN1 splice variants and GluN2 NMDA subunits that can influence the
alcohol sensitivity of these receptors (80,81). Blockade of excitatory NMDA
signaling is likely to be important in mediating some of the acute behavioral
actions of alcohol. This behavioral action has been tested using mice genetically
modified to express an NMDA GluN1 subunit with a transmembrane domain
mutation that reduces ethanol inhibition. These mice show reduced sensitivity to
some actions of ethanol (locomotor activation, motor incoordination, anxiolysis),
while others (loss of righting reflex, sleep time, hypothermia) are not affected
(82). In addition, these mutant mice show changes in ethanol consumption
supporting the idea that acute inhibition of NMDA receptors during drinking is
one important factor that regulates drinking. Inhibition of NMDA receptors in
the prefrontal cortex may underlie some of the cognitive deficits and errors in
judgment observed during alcohol intoxication (72,83,84). Long-term alcohol
consumption may also affect NMDA receptors in medial and orbital cortical
areas that are important for adapting behavior to rapidly changing contingencies
(54,85,86). The antagonism of NMDA receptors by alcohol may also be
involved in its rewarding properties because NMDA receptors are thought to be
important in regulating the release of dopamine in mesolimbic areas such as the
nucleus accumbens. For example, using microdialysis to monitor changes in
dopamine in awake animals, NMDA antagonists were shown to increase levels
of dopamine in the nucleus accumbens (87). These results suggest that
glutamate, by acting on NMDA receptors on interneurons, may exert an
inhibitory control over dopamine release by NMDA receptors. Relief of this
inhibition during exposure to alcohol may lead to increases in accumbens
dopamine. In animal studies designed to evaluate the subjective effects of
ethanol on behavior, NMDA antagonists can produce ethanol-appropriate lever
response in rats trained to discriminate ethanol from saline (88).
Since NMDA receptor activity is a critical determinant of normal neuronal
activity, it is perhaps not surprising that receptor function is also altered
following chronic exposure to alcohol. In primary cultures of neurons, chronic
exposure to alcohol increases the density and clustering of NMDA but not non-
NMDA receptors (89–91). These changes appear to take place specifically
within the glutamatergic synapse as there is no change in NMDA receptors in
nonsynaptic locations. These results suggest that NMDA receptors may serve as
alcohol sensors and that neurons compensate for inhibition of these receptors by
moving more of them to the synapse where they can be activated by glutamate.
One important outcome of this adaptive response is an increased susceptibility of
animals and humans to seizures that develop during withdrawal from alcohol.
Experiments with mice show that NMDA-induced seizure activity is elevated in
mice made physically dependent on alcohol and that NMDA antagonists reduce
or prevent seizures during withdrawal (92). Results from studies using isolated
cells or intact animals also suggest that the enhancement in NMDA receptor
function after chronic alcohol may involve changes in the expression pattern of
specific NMDA receptor subunits (85,93–96).
Other Ion Channel Subtypes

5HT3 Receptors
5HT3 receptors are ligand-gated ion channels activated by serotonin. They are
permeable primarily to monovalent cations, such as sodium and potassium. In
cultured neurons and recombinant expression systems, low doses of alcohol
appear to potentiate currents carried by 5HT3 receptor (97,98). In behavioral
studies involving both rats and pigeons, 5HT3 receptor antagonists blocked the
animal’s ability to discriminate ethanol from saline, suggesting that alcohol’s
acute actions on 5HT3 receptors may underlie some of the subjective effects of
alcohol (99). Human studies using the 5HT3 antagonist ondansetron (Zofran)
have generally found the drug reduces drinking although this effect appears more
efficacious in early-onset alcohol use disorder (100).
Acetylcholine Nicotinic Receptors

Acetylcholine activates a family of ligand-gated ion channels expressed in brain
neurons that are related to the nicotinic receptor expressed at the neuromuscular
junction (101). Alcohol has been shown to either potentiate or inhibit
acetylcholine receptors expressed in cultured neurons or oocytes (102,103). In
neurons, this biphasic effect appears to result from expression of different
subtypes of nicotinic receptors that show a differential response to ethanol. Thus,
heteromeric nicotinic receptors composed of αβ subunits appear to be
potentiated by ethanol, whereas homomeric receptors composed of just α
subunits (α7, eg) are inhibited by ethanol (103). It is not yet clear how these
different effects of ethanol on neuronal nicotinic receptors are manifested at the
behavioral level. However, nicotinic receptors are expressed by neurons in the
VTA, nucleus accumbens, and prefrontal cortex where they help shape the
excitability of these neurons. Varenicline (Chantix), a medication approved for
tobacco use disorder, is a partial agonist at the α4β2 nicotinic receptor. Results
from preclinical studies have reported that varenicline reduces alcohol seeking in
rodents without altering responding for sucrose (104). Human trials have also
supported the efficacy of varenicline in alcohol use disorder (105–107).
ATP-Gated Ion Channels

Adenosine triphosphate (ATP) is released into synapses where it acts on ATP-
gated ion channels of the P2X family (108). Alcohol inhibits ATP-gated
channels in some neurons (109), while the effect of alcohol on recombinant P2X
receptors is subtype specific. P2X2 and P2X4 channels are inhibited by alcohol
(109–111), but currents from P2X3 receptors are enhanced (112). This appears to
involve differences in a small number of amino acids between subunits at sites
near the transmembrane domains that control channel gating (113). The
inhibitory action of ethanol on the P2X4 receptor is blocked by the anthelmintic
drug ivermectin that is a positive allosteric modulator of P2X4 channel function
(114). In mice, ivermectin reduces ethanol consumption in a variety of drinking
models (115).
Potassium and Calcium Selective Ion Channels

Potassium channels that are regulated by calcium (SK and BK channels) and
those gated by G protein (GirK) channels are also affected either directly or
indirectly by alcohol (116). Potassium channels serve as a brake on excitatory
glutamatergic transmission by hyperpolarizing the membrane and thus are
critical regulators of neuronal activity. BK channel activity is acutely enhanced
by alcohol, and this enhancement may contribute to the inhibition of vasopressin
release from neurohypophysial terminals and the resulting diuresis that
accompanies alcohol ingestion (116). SK channels do not appear to be inhibited
directly by ethanol, but their function appears to be down-regulated in
hippocampal and orbitofrontal cortex neurons following chronic exposure to
ethanol (54,117). As these channels help repolarize the neuron membrane
potential after action potentials, reductions in SK channel expression may
contribute to the hyperexcitability often observed during ethanol withdrawal.
Down-regulation of SK channels in nucleus accumbens following chronic
alcohol exposure may contribute to elevated drinking as enhancing SK activity
in this area with an allosteric modulator (chlorzoxazone; Parafon Forte) reduced
alcohol consumption in rats (118). In contrast, inhibiting SK2 channels in the rat
infralimbic prefrontal cortex enhanced the extinction of alcohol-seeking
behavior (119). Together, these findings suggest that while SK2 modulators may
represent a novel means of treating alcohol use disorders, their efficacy may
depend on whether subjects are actively drinking or are abstinent. Most voltage-
gated potassium and sodium channels are relatively insensitive to relevant
concentrations of alcohol although there are exceptions. For example,
recombinant Kv7 (previously termed KCNQ) channels are inhibited by moderate
concentrations of ethanol (120) and Kv7.2/Kv7.3 heteromers are thought to
underlie the slow, noninactivating M-current that reduces neuronal excitability.
In VTA DA neurons, M-current is inhibited by acute ethanol at concentrations
that enhance DA neuron firing suggesting another possible mechanism for
ethanol-induced increases in DA release (121). Alcohol also has inhibitory
actions on certain subtypes of voltage-gate calcium channels (122), and
genetically modified mice lacking the N-type calcium channel show reduced
ethanol consumption as compared to wild-type animals (123). Alterations in T-
type calcium channels in thalamic neurons by alcohol may contribute to
disruptions in sleep that are commonly observed in individuals with alcohol use
disorder (124).
Pharmacological Studies Implicating Other

Neurotransmitter Systems
Much of the working knowledge of alcohol’s effects on neuronal function comes
from animal studies examining the effects of neurotransmitter-specific agents on
alcohol drinking. A brief review of this literature is presented here and is
summarized in Table 9-4.
Table 9-4 Alcohol Interactions with Brain

Neurotransmitter Systems
The table summarizes effects of acute and chronic alcohol on various brain ion channels and
neurotransmitter signaling systems. Right column lists alcohol-related behaviors that each
system/neurotransmitter may contribute to.
Adenosine
Adenosine is a major inhibitory neurotransmitter in the brain and may serve as
an endogenous antiepileptic because of its ability to inhibit neuronal function.
Alcohol has been shown to inhibit the function of a nucleoside transporter,
leading to increased extracellular adenosine levels (125). This leads to activation
of A2 adenosine receptors and increases cellular levels of cAMP that can
activate PKA and stimulate cAMP-dependent changes in gene expression. A2
receptors show crosstalk with D2 dopamine receptors and this interaction may
be especially important in regulating the activity of medium spiny neurons in the
nucleus accumbens. Block of this signaling pathway has been shown to reduce
voluntary alcohol drinking in experimental animals (126).
Dopamine
As mentioned earlier in this chapter, increases in the activity of mesolimbic
projecting dopamine neurons is thought to be a critical step underlying the
reinforcing effects of many drugs, including alcohol (23). Electrophysiological
studies have demonstrated that alcohol increases the firing of dopamine-
containing neurons, located in the VTA leading to enhanced dopamine release in
the nucleus accumbens (28). The mechanism underlying this effect of alcohol is
not precisely known but may involve both a direct effect on a subtype of
potassium channel that regulates the excitability of VTA neurons (29) as well as
indirectly via modulation of inputs into the VTA. Interestingly, the sensitivity of
VTA neurons to alcohol-induced excitation is lower in mice that show a higher
voluntary consumption of alcohol, suggesting that these animals may consume
more alcohol to sufficiently activate a dopaminergic reward pathway (28,127). In
addition, recent studies using retrograde tracers to identify subpopulations of
VTA DA neurons reveal that those projecting to nucleus accumbens but not to
prefrontal cortex show changes in glutamatergic plasticity following brief
exposure to drugs such as cocaine or toluene (32,128). These findings point out
that DA neurons within midbrain areas have specialized roles with respect to
control of reward-based behaviors.
The role of dopamine in alcohol addiction has also been explored by using
pharmacological agonists and antagonists that directly interact with dopamine
receptors. The long-acting dopamine agonist bromocriptine (Parlodel),
administered systemically, shift’s a rat’s preference from alcohol to water,
especially in those strains of rats that show alcohol preference (129). Similar
findings were demonstrated with another dopamine agonist, apomorphine. These
results suggested that administration of direct dopamine agonists reduced the
need for alcohol’s dopamine-enhancing activity in these animals, such that the
“reward state” was achieved at lower alcohol levels. Despite these promising
results, human studies with these agents have not found significant effects on
alcohol drinking or relapse (100).
Opioids and Other Neuropeptides

The involvement of endogenous opioids (endorphins, enkephalins, dynorphin)
and other neuropeptides in alcohol addiction is suggested by several lines of
research. One of the first links between alcohol and opioids was suggested by the
finding that acetaldehyde could undergo a metabolic reaction with monoamines
to form compounds (tetrahydroisoquinolines or TIQs) that were structurally
related to morphine (130). TIQs were shown to elicit alcohol-drinking behavior
and alcohol preference even after cessation of TIQ administration (131). This
hypothesis, although attractive, remains controversial because of the inability to
replicate some of these findings, and the demonstration that TIQ formation in
vivo may arise from dietary factors rather than direct effects of alcohol (132).
Alcohol does increase the release of certain opioid peptides (such as endorphin)
from rat pituitary glands and increases blood levels of endorphins in humans
(133). If alcohol drinking is mediated in part by opioids, then selective opioid
antagonists should inhibit alcohol-drinking behavior. Naloxone and naltrexone,
two opioid receptor antagonists, reduce alcohol intake in both animals and
humans, and various formulations of naltrexone (ReVia), including sustained-
release and depot forms (Vivitrol, Naltrel, Depotrex), are now approved for
treating alcoholism. These agents are thought to work by blocking alcohol-
induced increases in β-endorphin thus reducing the acute rewarding effects of
alcohol. As reviewed in a later chapter, a large number of laboratory studies and
randomized, controlled trials have been conducted and most of these report that
naltrexone, when combined with medical management is better than placebo in
reducing the risk of relapse (134). The results from these human studies are
complemented by those using mice genetically modified to lack the μ-opiate
receptor. These animals do not self-administer alcohol or respond to the
rewarding effects of opioids, nicotine, or cannabinoids (135). Despite these
dramatic effects in animal models and positive results in most human trials, the
clinical efficacy of nonselective opioid antagonists in treating alcohol use
disorder is rather modest suggesting that other factors may be important
(100,136). As discussed in more detail in a later chapter, the variability in
response to these antagonists may be due to issues related to compliance as well
as in differences in opioid receptor polymorphisms and other genetic changes
among subjects with alcohol use disorder that influence naltrexone efficacy
(100,137). In addition to naltrexone and related compounds, there is mounting
evidence that antagonists of the kappa receptor may have clinical efficacy under
certain conditions. Kappa receptors are activated by the opioid peptide
dynorphin that is suggested to be involved aspects of negative reinforcement
such as during withdrawal from alcohol and other addictive substances. Kappa
receptor antagonists reduce alcohol self-administration in rodents, including that
induced or augmented by stress (138,139).
Other neuropeptides such as NPY and CRF are involved in mediating stress
and anxiety and have been shown to be important regulators of alcohol drinking.
CRF is released following activation of the hypothalamic–pituitary–adrenal
(HPA) axis leading to elevated levels of cortisol that are indicative of a stress
response. Alcohol also induces CRF release and chronic alcohol use is
associated with enhanced anxiogenesis that can be blocked by CRF antagonists
(140). CRF antagonists appear to be especially effective in reducing the elevated
drinking observed in alcohol-dependent rats without altering consumption in
nondependent animals (141). Mice engineered to lack CRF1 receptors do not
show enhanced drinking following the development of physical dependence
again suggesting an important link between stress and alcohol drinking (142).
Despite the compelling evidence from preclinical studies, two different CRF1
antagonists (pexacerfont and verucerfont) failed to reduce cue-induced craving
for alcohol in human clinical trials (143,144). NPY is a neuropeptide associated
with the general regulation of feeding behavior and anxiety. Injection of NPY
reduces drinking in rodents, while mice lacking NPY or the NPY Y1 receptor
display enhanced ethanol intake (145). These effects may be related to anxiolytic
effects of NPY. In addition to CRF and NPY, a variety of studies have shown
that the neuropeptide orexin (also called hypocretin) influences drinking. Orexin
is synthesized by a small number of neurons in the lateral hypothalamus and
axons from these neurons innervate a wide array of brain structures including
those involved in reward and cognition. Studies in rodents shows that orexin
antagonists can reduce drinking with greatest efficacy in alcohol-preferring
individuals (146,147).
Serotonin
As mentioned above, electrophysiological studies have demonstrated that
alcohol enhances cation conductance through 5HT3 receptors (97). Serotonin
also interacts with a large number of non–ion channel G protein–linked receptors
that are coupled to various signal transduction pathways. The direct effects of
alcohol on these receptor systems are not as well characterized. However, there
is a fairly large amount of literature describing the effects on alcohol-drinking
behavior of various drugs that modulate serotonergic tone. 5HT and 5HT-
metabolite levels are reduced in the cerebrospinal fluid of many alcohol abusers,
suggesting that reduced 5HT levels or a reduction in 5HT-mediated
neurotransmission may predispose certain people to uncontrollable drinking
behavior (148).
It has been suggested that similar deficiencies in 5HT neurotransmission
underlie the development of a variety of other disorders, including bulimia and
obsessive–compulsive behavior, disorders that are characterized by a loss of
behavioral control. Thus, pharmacological agents that enhance 5HT
neurotransmission (such as serotonin selective-uptake inhibitors) appear to be
therapeutically effective in the treatment of these disorders. However, in terms of
treating alcohol use disorder, these agents (such as fluoxetine, Prozac and
sertraline, Zoloft) appear to have limited efficacy (149,150). Of course, one
drawback in using a transport inhibitor is the inability to selectively activate
specific subtypes of 5HT receptors. Interestingly, a variety of results from animal
studies suggest that the 5HT1b receptor may be especially involved in regulating
alcohol intake although the data are conflicting regarding whether receptor
activity should be enhanced or blocked to produce these effects (151–153). In
addition, it is not completely clear whether these manipulations are selective for
alcohol as 5HT plays a central role in feeding and drinking behaviors.
Metabotropic Glutamate Receptors

In addition to its direct effect on ionotropic glutamate-activated ion channels
such as the NMDA receptor, there is evidence that metabotropic mGluR
receptors play a role in alcohol action. These receptors are G protein–coupled
glutamate receptors and are expressed at both pre- and postsynaptic sites where
they influence excitability by reducing neurotransmitter release and regulating
membrane excitability. The presynaptic mGluR2 subtype is particularly
interesting as several recent studies have implicated it as an important mediator
of drinking. P rats previously generated by selective breeding for high alcohol
consumption were found to express a premature stop codon in the Grm2 gene
leading to a loss of expression and function of mGluR2 receptors (154).
Pharmacological block of mGluR2 receptors in control rats enhanced alcohol
consumption (154), and alcohol-dependent animals show a reduction in mGluR2
expression in certain areas of the prefrontal cortex that may regulate drinking
(155).
Endocannabinoids
An extensive series of studies have shown that the endogenous cannabinoid (EC)
system is an important modulator of ethanol drinking (156). ECs are natural
lipid-derived molecules that activate receptors (CB1, CB2) that also bind THC,
the psychoactive constituent of marijuana. ECs regulate both GABAergic and
glutamatergic synaptic transmission and are synthesized during periods of
intense neuronal depolarization. CB1 agonists including THC are powerful
appetite promoting compounds and antagonists of the CB1 receptor (rimonabant,
Acomplia) were initially marketed in Europe for treatment of obesity. However,
this drug and others in the same class were removed from the market due to
significant psychiatric effects (157). In animal studies, CB1 antagonists such as
rimonabant reduce ethanol preference in wild-type mice and animals that lack
CB1 receptors show reduced alcohol preference (158). This action may reflect
the ability of these compounds to block the alcohol-induced increase in
dopamine in the nucleus accumbens (159). This effect was also observed for
cocaine and nicotine-induced increases in dopamine suggesting a link between
the EC system and a variety of addictive drugs that possess disparate acute
mechanisms of action.
Neuroimmune Modulators
Mediators of immune function have recently been implicated as important
determinants of alcohol-induced neurodegeneration and may also influence brain
systems that regulate ethanol intake. Of these, the family of Toll-like receptors
(TLR) and the receptor for advanced glycation end products (RAGE) have been
shown to be particularly involved in the brain’s response to alcohol. For
example, genetically modified mice that lack the TLR4 receptor show reduced
neurodegeneration following chronic exposure to ethanol and show blunted
expression of neuroimmune genes (160). In wild-type mice, repeated exposures
to binge-like levels of alcohol induced the expression of TLR receptors
including TL4 and activators of TLR signaling such as HMGB1 (161). Similar
increases have been reported in postmortem brains from individuals with DSM-
defined alcohol dependence (161). These changes were correlated with the age
of drinking onset and the lifetime consumption of alcohol with individuals who
started drinking earlier and those who consumed the most ethanol showing
higher expression (161,162). While changes in immune signaling molecules in
brain likely reflect direct actions of ethanol on brain, ethanol also induces
HMGB1-TLR4 signaling in the gut with subsequent leakage of bacterial
products that are powerful stimulators of the innate immune system (163). These
mediators then appear to be transported across the blood brain barrier where they
induce proinflammatory responses. Changes in gut permeability appear to
require relatively high concentrations of ethanol that are associated with binge
drinking of alcoholic beverages with high alcohol content. Agents that target
different aspects of neuroimmune signaling are currently being tested for their
ability to reduce ethanol-induced neurodegeneration and elevated levels of
drinking.
ADDICTION LIABILITY
Alcohol is an addictive substance although an individual’s susceptibility to
developing alcohol use disorders is influenced by a wide range of genetic and
environmental factors. The 12-month prevalence for DSM-defined alcohol
dependence for males is about 5.4% for men and 2.3% for women (164).
Lifetime prevalence of alcohol dependence is ~13%, and the risk of developing
alcohol dependence shows a strong inverse correlation with the age at which
heavy drinking begins (164). Chronic use of alcohol produces several
neuroadaptive changes that may be important in the development of alcohol
addiction.
Sensitization
Sensitization is defined as an increase in the pharmacological and physiological
response to a drug after repeated exposures. This phenomenon is best
characterized by addictive drugs such as cocaine or amphetamine where
enhanced locomotor activity following repeated drug exposures is associated
with changes in glutamatergic signaling in the neurons of the VTA and nucleus
accumbens (25). Sensitization to the locomotor effects of alcohol has also been
well studied, and the magnitude and duration of these effects depend on
genotypic and environmental factors (165,166). Another form of sensitization is
characterized by an increase in the severity and intensity of withdrawal signs
after multiple episodes of alcohol intoxication and withdrawal (167). This form
of sensitization has been suggested to be similar to the kindling phenomena
observed after repeated brain seizures and may involve some of the same
mechanisms that underlie the adaptation of neurons to impaired neuronal
signaling during chronic exposure to alcohol.
Tolerance and Dependence

Tolerance is manifested as a reduced sensitivity to alcohol and is subdivided into
several forms, depending on the specific action being measured and the time
course over which it develops. For example, concentrations of alcohol required
to produce sedation may increase in individuals or animals given alcohol
chronically. In human alcoholics, tolerance to the sedative and even lethal effects
of alcohol can be profound. For example, while the lethal dose 50% (LD50) in
nontolerant humans is ~400-500 mg%, blood levels exceeding these values are
often reported in individuals arrested for drunk driving (168). This form of
tolerance is associated with changes in both the capacity to metabolize alcohol
and in cellular adaptations that reduce sensitivity to alcohol. A form of short-
term acute functional tolerance to alcohol (termed the “Mellanby effect”) is also
demonstrated by differences in the degree of impairment produced by the same
blood concentration of alcohol achieved during the rising phase of the blood
alcohol curve as compared to the falling phase (169). Tolerance development has
been extensively studied in rodent models, and the severity of the motor
impairing effects of alcohol is strongly influenced by the context and
environment in which they are measured (170). Physical dependence is defined
by the occurrence of symptoms that appear after the cessation of alcohol
drinking. Withdrawal symptoms include both physical (tremors, convulsions)
and psychological (negative emotions, craving) components. At the cellular
level, tolerance and dependence also develop so that the acute effects of alcohol
on ion channel or receptor function are diminished in animals chronically
exposed to alcohol. As mentioned in the earlier section, this adaptation may
involve changes in signaling pathways that regulate subunit expression or the
functional state of alcohol-sensitive ion channels as neurons adapt to the chronic
presence of alcohol (171,172). Although reward mechanisms are undoubtedly
important in the development of heavy alcohol use, processes and brain areas
that underlie the development of addiction may be critical for maintaining
continued drinking through negative reinforcement (anxiety, stress) generated
during withdrawal. In support of this idea, a variety of studies now implicate
activation of brain areas such as the amygdala and associated structures
(“extended amygdala”) with a relapse to drinking precipitated by alcohol
specific cues or stress (173). These areas in combination with brain stress
systems and areas involved in decision-making (prefrontal cortex) may be
critically important in driving continued drinking in individuals with alcohol use
disorder (24).
A main feature of human alcohol use disorder is the strong desire or craving
for alcohol. Bouts of heavy drinking often follow periods of abstinence even
when the symptoms of alcohol withdrawal have long subsided. This occurrence
suggests that prolonged alcohol use may involve long-lasting or permanent
changes in brain systems that alter a person’s responsiveness to alcohol. Animal
models of craving and relapse have been established and involve measuring
consumption in alcohol-trained animals after various periods of deprivation
(27,174). In most cases, animals display a robust increase in alcohol
consumption after deprivation, and this effect is characterized by not only higher
rates of drinking but also increased preference for solutions containing higher
alcohol concentrations. In addition, the alcohol deprivation effect in animals
persists for very long periods of abstinence (up to 9 months; about 1/3 the
lifespan of a rat), suggesting long-lasting or even irreversible changes in
mechanisms regulating drinking behavior. Several studies have shown that drugs
currently approved for treatment of alcohol use disorder such as calcium N-
acetyl homotaurine (acamprosate; Campral) and naltrexone (ReVia) can reduce
or reverse the increase in ethanol intake produced by periods of forced
deprivation (27). These results are important as they validate the utility and
predictive value of animal models of craving and relapse and offer hope for the
identification of better pharmacological treatments to reduce or prevent relapse
to drinking following withdrawal.
Toxicity States
Alcohol produces a well-studied progression of behavioral symptoms that are
highly correlated with blood alcohol levels. In nontolerant individuals, low
levels (10-50 mg%) are anxiolytic and produce a feeling of well-being and
increased sociability. As levels increase to 80-100 mg%, there is increased
release from inhibitions and signs of impaired judgment and motor function.
Higher levels (150-200 mg%) produce marked ataxia and reduced reaction time,
and some individuals may experience blackouts, postintoxication periods where
the individual cannot recall events that occurred during intoxication. As levels
reach and exceed 300 mg%, an anesthetic level is approached and individuals
may show severe motor impairment and vomiting. As mentioned previously,
lethal doses of alcohol in nontolerant individuals are on the order of 400-500
mg% although this can vary widely. Alcohol is metabolized under zero order
kinetics such that it is independent of dose and time and blood alcohol levels fall
at a rate of about 20 mg/dL/h in a nontolerant person. This rate can be higher in
patients with significant tolerance as part of their alcohol use disorder.
Medical Complications
Alcohol affects nearly all tissue and organ systems studied, and heavy drinkers
show skeletal fragility and damage to tissues such as the brain, liver, and heart,
as well as increased susceptibility to some cancers. Despite these negative
effects, beneficial effects of moderate alcohol intake have been demonstrated;
these include a reduced risk of coronary heart disease in individuals classified as
light to moderate drinkers. Two factors that are important in determining
whether alcohol drinking is associated with positive or negative effects are how
an individual drinks and for how long. Most beneficial effects of alcohol are
associated with light to moderate drinking, consisting of two or fewer drinks per
day for men and one or less per day for women. These amounts are well below
those with alcohol use disorders, who may consume more than 10-12 drinks per
day. At higher levels, significant toxicity develops in most tissues, including the
brain.
A variety of brain imaging techniques have been applied to the study of
alcohol use disorder. These techniques include computed tomography, magnetic
resonance imaging (MRI), single-photon emission computed tomography
(SPECT), and positron emission tomography (PET). Results from studies of
human alcoholics has revealed increases in cortical cerebrospinal fluid in both
gray and white matter that is distinct from that found in other neuropsychiatric
disorders such as schizophrenia and Alzheimer disease (175,176). When
corrected for age-related changes in these parameters, the frontal lobes and
cerebellar gray matter are particularly sensitive to alcohol-induced damage. MRI
studies have shown that volume deficits are found in anterior but not poster
hippocampus and that these deficits were more severe in patients who displayed
symptoms of memory loss and possible Korsakoff syndrome. Prenatal as well as
adult exposure to alcohol was shown to disrupt and reduce the area of the corpus
callosum. Functional imaging techniques such as magnetic resonance
spectroscopy (MRS) or PET have been used to study alcohol-related changes in
brain function (177,178). These techniques monitor the levels of certain
metabolites (N-acetyl aspartate and myo-inositol) or glucose metabolism that
give useful information as to the integrity and functional status of the brain.
These and other studies show reduced brain glucose metabolism in untreated
patients with alcohol use disorder as compared with control subjects. Brain
glucose metabolism has also been shown to increase 16-30 days after
withdrawal, consistent with improvements in neuronal integrity measured by
MRI. SPECT studies can detect changes in cerebral blood flow and have shown
that patients with alcohol use disorder may have low perfusion of frontal lobe
areas. Changes in blood flow coupled with structural damage to frontal brain
areas may underlie the changes in cognitive and emotional behaviors observed in
these patients.
Although a lifetime of heavy drinking long has been known to produce
substantial changes in brain neuron density, recent data obtained in animal
studies suggest that brief episodes of heavy drinking, or binges, also cause
neuron loss (179). These findings are particularly relevant to alcohol use during
adolescence and young adulthood as these episodes of heavy binge drinking
occur during critical periods of brain development (180).
The mechanisms underlying ethanol-induced neurotoxicity are not
completely understood. There is a consensus that some forms of alcohol-induced
damage may arise from overactivation of NMDA receptors during alcohol
withdrawal. Thus, chronic exposure of neurons to ethanol induces an up-
regulation in the functional status of the NMDA receptor that is revealed during
withdrawal (181,182). Enhanced receptor activation by glutamate may lead to
above-normal production of cellular signals that contribute to cell death.
In other cases of ethanol-induced neurotoxicity, it appears that a non–
NMDA-mediated mechanism is at work. In an acute binge model of alcohol
intoxication, rats given large doses of alcohol over a 3- to 4-day period show
pronounced loss of neurons in specific brain areas, including the entorhinal
cortex and dentate gyrus. The toxic actions of ethanol were not blocked by
NMDA antagonists but were attenuated by the diuretic furosemide (Lasix),
suggesting other pathways for ethanol-induced brain damage (183). Chronic
alcohol drinking may also induce activation of microglia and astrocytes in brain
tissue and promote aberrant signaling of the neuroimmune system (184). This
may lead to overexpression of proinflammatory molecules such as cytokines,
oxidases, and proteases that contribute to dysfunctional frontal circuits observed
in patients with alcohol use disorder.
Heavy alcohol use during pregnancy can lead to a variety of birth defects
and alterations in normal growth and development of the newborn (185). Fetal
alcohol spectrum disorder (FASD) consists of a variety of characteristic
symptoms in newborns exposed to alcohol in utero and one in three infants born
to mothers with alcohol use disorder display symptoms of FASD. These
symptoms include CNS dysfunction, such as low IQ and microcephaly, delayed
growth, and facial abnormalities, among others. FASD generally is associated
with heavy drinking, especially early in pregnancy, although it is not known if
there is any safe lower limit for alcohol consumption.
CONCLUSIONS/FUTURE RESEARCH
It is clear that a great deal of progress has been made in recent years in
understanding the sites and mechanisms of alcohol’s effects on the brain. There
is a growing appreciation that alcohol and other drugs initially target brain
circuits involved in reward and learning and with repeated use causes long-
lasting changes in areas involved in habit formation, stress, and cognitive control
of behavior. With regard to sites of action, a consensus has emerged that specific
ligand-gated and voltage-gated ion channels represent a likely site for many of
the acute effects of alcohol on neuronal function although exactly how alcohol
produces these effects remains unclear. Compensatory mechanisms of
neuroplasticity are likely engaged during repeated episodes of alcohol drinking
and withdrawal as neurons and neuronal circuits attempt to adapt to the periodic
presence of alcohol. These effects may involve changes in the expression and
distribution of ion channel subunits and their downstream signaling processes
that are normally involved in allowing an organism to learn and adapt to its
environment. Chronic use of alcohol may usurp these mechanisms and result in a
near permanent altered neuropsychological state that promotes continued alcohol
consumption. More work is needed with transgenic or knock-in animals that
express proteins with altered alcohol sensitivity, so as to better understand the
correlation between these targets and alcohol’s behavioral effects. For example,
if ion channels gated by glutamate, GABA, acetylcholine, ATP, and serotonin
represent primary targets of alcohol action, how does perturbation of these
channels lead to behaviors such as reward, craving, and reinforcement that
appear to involve complex neurocircuitry and multiple neurotransmitters such as
dopamine, opioids, and neuropeptides?
Other areas that need attention include elucidating the normal physiological
processes that operate in response to food and other natural reinforcers, as well
as what genetic and environmental factors contribute to an individual’s risk for
developing an alcohol use disorder. Better use of brain imaging techniques in
conjunction with electrophysiological recording and network modeling would
also improve our understanding of the neural regions that are involved in
mediating the various behaviors associated with alcohol use disorder. As
outlined in later chapters, more effort is needed to develop better
pharmacological treatments for alcohol use disorder including those that can
target the different subtypes of alcoholism that may respond differentially to
currently available compounds. Lastly, there needs to be enhanced emphasis and
support for more research into the causes and treatments of alcoholism and better
public awareness that alcohol use disorder is a chronic relapsing disease that,
like other chronic diseases, can be treated.
ACKNOWLEDGMENTS
Development of this chapter was supported by grant R37AA009986 and
P50AA10761 from the National Institute on Alcohol Abuse and Alcoholism.
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CHAPTER 10
The Pharmacology of Nonalcohol
Sedative Hypnotics
Carolina L. Haass-Koffler and Elinore F. McCance-Katz
CHAPTER OUTLINE
Formulations and Chemical Structure
Brief Historical Features
Pharmacodynamics
Pharmacokinetics
Pharmacogenomics
Special Consideration of Concomitant Use of Benzodiazepines and Opioids
Mechanism of Tolerance and Withdrawal
Addiction Liability
Epidemiology of Unhealthy Use
Toxicities
Medical Complications
Conclusion
Sedative hypnotic drugs represent a diverse group of chemical agents that

depress the function of the central nervous system (CNS) (1). They are used in
medicine as anxiolytics, sleep inducers, hypnotics, anticonvulsants, muscle
relaxants, and anesthesia induction agents. Their calming (sedative) effects are
dose dependent and on a continuum with sleep-inducing (hypnotic) effects,
unconsciousness, and, for some agents, coma and death. Agents discussed in this
chapter include benzodiazepines, nonbenzodiazepine hypnotics, and
miscellaneous related compounds.
FORMULATIONS AND CHEMICAL

STRUCTURE
The name benzodiazepine is derived from the chemical structure comprised by a
benzene ring fused to a seven-membered diazepine ring (Fig. 10-1) (2).
Modification in the ring system has yielded compounds with altered potency and
efficacy (3).
Figure 10-1 The core structure of benzodiazepines comprised
by a benzene ring fused to a seven-membered diazepine ring.
The “R” groups denote side chains of which yielded
compounds with altered potency and efficacy.
The more recent sedative hypnotic agents include the nonbenzodiazepines (eg,
zopiclone, eszopiclone, zaleplon, and zolpidem). While the chemical structure of
these compounds is not similar to the benzodiazepines, their therapeutic effect is
via benzodiazepine binding site at the γ-aminobutyric acid (GABAA) receptor;
their actions are not identical to classic benzodiazepines. The clinically available
formulations of benzodiazepines and nonbenzodiazepines, half-life (t1/2),
biotransformation, and active metabolites are shown in Table 10-1.
Table 10-1 Elimination Half-Life (t1/2), Cytochrome

P450 Enzymes (CYP) that Mediate Metabolism and
Production of Active Metabolites
DMD, desmethyldiazepam; t1/2, half-life in minutes.
BRIEF HISTORICAL FEATURES

In the 1950s, the synthesis of chlordiazepoxide with hypnotic, sedative, and
muscle-relaxant effects opened the era of benzodiazepines. In 1960,
chlordiazepoxide was marketed as Librium, a safe and effective anxiolytic agent.
The elimination of the basic nitrogen moiety, from the original structure,
increased the potency of chlordiazepoxide by threefold to tenfold and produced
diazepam, which was marketed in 1963 as the popular drug Valium. The
widespread clinical use of benzodiazepines as anxiety-relieving and sleep-
inducing medications was well established by the end of the 1970s when
benzodiazepines were found to account for 10% of all prescriptions written in
the United States (4).
The benzodiazepines, to a great extent, have replaced the barbiturates, which
have a low therapeutic/toxic ratio and exert depressant effects on the
cerebrospinal axis and neuronal activity, skeletal muscle, smooth muscle, and
cardiac muscle activity with substantial risk for adverse events. Furthermore,
benzodiazepines are less toxic in overdose, have less capacity to produce fatal
CNS effects, and are associated with fewer drug interactions.
Nonbenzodiazepine hypnotics have been the most recent addition to this group
of drugs, and they are more potent than the benzodiazepines. They may offer an
advantage of lower liability for unhealthy use, though clinical experience is
insufficient to make definitive judgments.
At the present time, benzodiazepines are widely utilized in the management
of many medical and psychiatric conditions and are often used for long periods
of times—for many patients, once started on these medications, they may be
maintained on them for years.
Conditions for which benzodiazepines are frequently used include acute
relief of anxiety and insomnia, which may extend to long-term, chronic use.
Benzodiazepines are often administered as adjuncts to anesthesia prior to surgery
and as muscle relaxants in pain management, for example, the treatment of low
back pain. Further, the United States Food and Drug Administration (FDA) has
approved the use of benzodiazepine medications for the treatment of panic
disorder and generalized anxiety disorder. Benzodiazepines also remain a
frequently utilized approach to management of acute agitation in psychiatric
syndromes, often in combination with antipsychotic medications. The multiple
clinical uses for benzodiazepines and the chronic nature of their use in many
patients have made benzodiazepines and nonbenzodiazepine hypnotics some of
the most frequently prescribed medications in the United States.
PHARMACODYNAMICS
Benzodiazepines and nonbenzodiazepines exert their clinical effects through
allosteric modulation of the GABAA receptor (5). As GABA is the major
inhibitory neurotransmitter system in the brain. Positive modulation of the
receptor by benzodiazepines is responsible for sedative, anticonvulsant,
hypnotic, and amnestic effects of the drug. The GABAA receptor is a
heteropentameric protein structure surrounding a central chloride channel (6).
The five subunits that are linked to form the chloride ion channel are classified
into several subtypes: alpha (α1–6), beta (β1–3), gamma (γ1–3), delta (δ), epsilon
(ε), rho (ρ), and pi (π), each of which has a unique sequence of amino acids and
determines the pharmacological properties of the receptor (6). In the human
brain, the most common structure of the GABAA receptor consists of two α, two
β, and one γ subunit (6). Benzodiazepines bind at the interface of the γ2 and α
subunits (5). GABAA receptors containing α1–3,5 subunits mediate effects of
benzodiazepines. Binding at the α1 subunit mediates sedative and amnestic
effects, while binding at the α2 (7) and possibly the α3 subunit (8,9) modulates
anxiolytic and muscle-relaxant effects. Anticonvulsant activity is modulated by
α1–3 subunits (10). The α5 subunit is located extrasynaptically and regulates tonic
GABAergic currents, while the other subunits are located predominately within
the synapse and mediate the rapid phasic GABA currents (11). In contrast, the
presence of α4 or α6 subunits leads to a lack of sensitivity to benzodiazepines.
The GABAA receptors that contain α1 have also been implicated in playing a
key role in the production of the ataxic effects of both benzodiazepines and
zolpidem (8,12). There is also evidence that the α2 and α3 subunits may mediate
the rewarding effects of diazepam (13). Other research, in contrast, has
implicated the α1 subunit in mediating the reinforcing effects of benzodiazepines
(14). Currently, FDA-approved nonbenzodiazepines are zolpidem, zaleplon, and
eszopiclone (S-enantiomer of zopiclone, not available in the United States).
Zolpidem is also formulated as an extended-release medication. This new
reduced-dose formulation is marketed for middle-of-the-night insomnia to
reduce next-day sedation. The nonbenzodiazepines may have less amnestic
effects and are less likely to be associated with the development of tolerance
compared to the classic benzodiazepines (15).
Nonbenzodiazepines share many pharmacological actions with
benzodiazepines including sedative–hypnotic, anxiolytic, myorelaxant, and
anticonvulsant effects, although their selectivity for these actions differs. For
example, animal studies suggest that zolpidem is more selective in its sedative
effects as compared to its anticonvulsant actions than are quazepam, zaleplon, or
zopiclone (16,17). Among the nonbenzodiazepines, eszopiclone has the
strongest antianxiety effect in animal models, which is produced at nonhypnotic
doses (18,19).
Benzodiazepines and nonbenzodiazepines may act through overlapping
binding sites between α and β subunits of the GABAA receptor (20–22).
Zolpidem, however, binds to additional sites on these subunits that are not
crucial for benzodiazepine activity (23–25).
Benzodiazepines have roughly similar affinities for GABAA subtype
receptors that contain the α1–3,5 subunits. In contrast, zaleplon and zolpidem
have more than tenfold greater affinity for receptors with an α1β2γ2 composition
than for those with an α2β2γ2 composition, whereas zopiclone has essentially
equivalent affinity for these receptors. Zolpidem in contrast to the
benzodiazepines and other nonbenzodiazepines has little affinity for α5-
containing GABAA receptors, and the presence of the γ3 subunit produces
insensitivity to zolpidem (26).
PHARMACOKINETICS
The effectiveness of a benzodiazepine as hypnotic is based on the
pharmacokinetic properties of the agent, which include the acute tolerance
developed, which will diminish CNS effects before the drug is eliminated; the
redistribution from the CNS to other peripheral tissues; and, finally, the rate of
biotransformation and formation of active metabolites.
Many benzodiazepines undergo hepatic metabolism involving oxidative
reactions mediated by the cytochrome P450 (CYP450) enzymes. Oxidative
metabolism reactions include N-dealkylation or aliphatic hydroxylation. The
CYP3A4 enzyme mediates the oxidative metabolism of many of the
benzodiazepines and also plays a role in the biotransformation of the
nonbenzodiazepine sedative–hypnotic agents. Several of the benzodiazepines are
converted into active metabolites such as desmethyldiazepam (DMD), which are
very slowly cleared from the body. The final phase of metabolism for most
benzodiazepines consists of conjugation of either the parent drug or their
metabolites with glucuronide. Drugs or metabolites that undergo glucuronidation
contain a hydroxyl group. Parent drugs, such as lorazepam and oxazepam, which
undergo direct glucuronidation, are less subject to drug interactions or reduced
clearance associated with impairment of hepatic function than are the other
benzodiazepines (27).
Distinct metabolic pathways appear to mediate the biotransformation of the
different nonbenzodiazepines. Zolpidem is extensively metabolized by CYP3A4,
CYP2C9, and CYP2C19 to inactive hydroxylated metabolites (28,29). Aldehyde
dehydrogenase may play a major role in the metabolism of zaleplon, which
involves the biotransformation of this drug into metabolites including 5-
oxozaleplon that are excreted into the urine. Nearly 50% of zopiclone is
transformed by esterase into a decarboxylated metabolite that is excreted through
the lungs. This drug is also converted by CYP3A4 into the active metabolite
zopiclone N-oxide and the inactive metabolite N-desmethylzopiclone.
The relationship between the pharmacokinetic profile of benzodiazepines
and risk for unhealthy use is complex. It is generally believed that rapid onset of
action is associated with euphoria (30). Onset of action after oral administration
relies on the formulation of the drug, the intrinsic activity of the drug, lipid
solubility, protein binding, and rate of entry into the brain. Some animal data
suggest that greater lipid solubility increases the rate of brain uptake, with
diazepam having more rapid brain uptake as compared to lorazepam (31). In
clinical practice, pharmacokinetic factors do not always predict risk for
unhealthy use. For example, clorazepate, rarely cited as a benzodiazepine with a
high risk for unhealthy use, is rapidly decarboxylated in the stomach to DMD,
which then reaches maximum plasma concentrations within 30 minutes or less,
and it has a long half-life (t1/2 = 40-50 hours) (32). Subjective ratings by people
who use substances of the “high” induced by clorazepate, however, are lower
than ratings for diazepam or lorazepam (33). Also, even though alprazolam and
oxazepam differ only slightly in lipid solubility (34–36), intrinsic activity and
rate of absorption are greater with alprazolam, which has higher potential for
unhealthy use than oxazepam (37–42). Lower risk for unhealthy use is more
consistently predicted with prodrugs that require hepatic metabolism to form the
active moiety, such as the formation of desmethyldiazepam from halazepam,
which appears to have lower risk for unhealthy use than diazepam (43).
Therefore, the rate of absorption and entry into the brain are factors that may
influence risk for unhealthy use.
PHARMACOGENOMICS
Pharmacogenomic investigation of benzodiazepines has focused on metabolizing
enzymes (44). The impact of polymorphisms in CYP3A4 and CYP3A5 on
benzodiazepine metabolism has produced mixed results. CYP3A4 and CYP3A5
genetic variations evaluated in healthy volunteers (45) and in vitro (46) did not
contribute to large interindividual variability in midazolam hydroxylation. On
the other hand, one in vitro midazolam study indicated that CYP3A4*16 showed
substrate-dependent altered kinetics compared with wild type (47).
Unlike CYP3A4/5, polymorphisms of CYP2C19 have been reported to have
more consistent impact on the metabolism of benzodiazepines. Poor
metabolizers had significantly lower plasma clearance of both diazepam and
desmethyldiazepam (48,49) and longer elimination half-life (50) when compared
to extensive metabolizers.
The most serious drug–drug interactions occur when sedative hypnotics are
combined with drugs that depress CNS activity (eg, alcohol, opioids, muscle
relaxants, etc.), potentially resulting in overdose and death. Benzodiazepines do
not induce their own metabolism; however, those that are metabolized through
CYP3A4 (Table 10-1) are subject to altered plasma levels by agents that inhibit
this metabolic pathway. Common inhibitors are ketoconazole, itraconazole,
macrolide antibiotics (erythromycin), fluoxetine, nefazodone, and cimetidine.
Drugs that induce or inhibit CYP2C19 may also influence the metabolism of
some benzodiazepines. For example, oral contraceptives containing estrogen and
progesterone impair the metabolism of some substrates of CYP1A2, CYP3A4,
and CYP2C19, although findings with benzodiazepines are inconsistent (51).
One study found inhibition of alprazolam metabolism in women taking low-dose
estrogen oral contraceptives (52), and another did not (53). Similarly, lorazepam
metabolism was unaffected by oral contraceptives in one study (54), yet
increased in another (52). The latter study also found enhanced elimination of
temazepam. Oxazepam kinetics are not affected by oral contraceptives (54). The
clearances of both chlordiazepoxide and diazepam are impaired in women taking
oral contraceptives (55–57).
Lorazepam and oxazepam are eliminated by glucuronidation and are not
substrates of the CYP450 system. As such, lorazepam’s kinetics in women
taking oral contraceptives is unaffected in one study (54); however, in another
study, both lorazepam’s metabolism and temazepam’s elimination were
enhanced (52). Oxazepam kinetics are not affected by oral contraceptives (54).
Inducers of CYP450 enzymes may significantly reduce plasma
concentrations of zaleplon, zolpidem, and zopiclone (28) or other
benzodiazepines that are CYP3A4 substrates. In particular, rifampin,
carbamazepine, and phenytoin have been shown to greatly decrease the
maximum serum concentration (Cmax) and area under the curve (AUC) of
midazolam (58,59). Similarly, repeated administration of the CYP3A4 inducer
carbamazepine increases the clearance of zolpidem (60).
Administration of the CYP3A4 enzyme inhibitors such as erythromycin or
ketoconazole, in contrast, can decrease the clearance of zolpidem (28).
Compounds, which inhibit CYP3A and CYP2C19 (eg, cimetidine, ketoconazole,
fluvoxamine, fluoxetine, and omeprazole), may lead to increased and prolonged
sedation with diazepam administration (59).
The ability of benzodiazepines to inhibit CYP450 enzymes has not been
extensively evaluated. One study found that flurazepam inhibits the organic
cation transporter 2 (OCT2, SLC22A2), which plays an important role for renal
drug elimination (61).
As the unhealthy use of prescription opioids has increased, the interaction
between opioids and sedative hypnotics has become an increasing concern.
There is extensive evidence implicating benzodiazepines in both fatal and
nonfatal cases of opioid overdose (62). Pharmacodynamic interactions between
benzodiazepines and opioids may lead to oversedation and impaired motor
performance. The combination of oxycodone and alprazolam, for example, when
coadministered at therapeutic doses produced greater impairment in
psychomotor performance and increased difficulty in concentrating than was
seen when these agents were administered alone (63). High-dose diazepam (40
mg) also enhanced psychomotor impairment and sedation when given
concurrently with either buprenorphine or methadone (64).
SPECIAL CONSIDERATION OF
CONCOMITANT USE OF
BENZODIAZEPINES AND OPIOIDS
Benzodiazepines have been increasingly linked to adverse events and deaths
when taken with opioids. In 2004, benzodiazepines were mentioned in 18% of
opioid overdose deaths, which increased to 31% by 2011 (65). From 1999 to
2013, the rate of prescription opioid-related deaths quadrupled. The majority of
these deaths involved the use of other drugs or alcohol with opioids.
Benzodiazepines were the most frequent medication class associated with opioid
overdose deaths (66).
One question that arises is why benzodiazepines are so frequently identified
as a secondary drug in an opioid-associated adverse event or death. Although
there is evidence of substantial nonmedical use of benzodiazepines as described
below (see Epidemiology of Unhealthy Use), it is also the case that
benzodiazepines are frequently prescribed for the treatment of pain and so may
be coprescribed with opioid analgesics. However, the limited studies that have
been conducted have shown little to no benefit of benzodiazepines in the
management of pain (67). One older study of alprazolam 1.5 mg daily for pain
management showed improvement in reported pain severity at 12 weeks (68).
However, other studies have shown no efficacy for benzodiazepines in treatment
of acute lumbar disc prolapse with sciatica (69) or for low back pain (70).
Studies in rodents showed that concomitant use of benzodiazepines was
associated with reduced morphine analgesia, which was blocked using the
GABAA antagonist, flumazenil (71). In humans administered diazepam
preoperatively, postoperative administration of flumazenil was shown to reduce
morphine analgesia requirements (72,73). In a study that examined concurrent
use of benzodiazepines in patients with chronic pain; it was reported that 38% of
the sample of 114 individuals were taking more than one benzodiazepine
medication, 46% had been using these medications for > 2 years, and the stated
reason for use was all or in part to assist with sleep. Interestingly, there was no
difference in reported sleep problems in those taking benzodiazepines as
compared to those in the sample who were not. However, while there were no
signs of excessive intake in those prescribed benzodiazepines; no individuals
were willing to stop taking these medications despite their reported lack of
effectiveness for insomnia (74). In a study of 1220 patients receiving chronic
opioid therapy, benzodiazepine use was examined. In this study, 33% of
participants had used benzodiazepines in the past month and 17% had used them
daily. Benzodiazepine use was associated with a number of adverse effects
including reports of greater pain severity, pain interference in life, and lower
feelings of self-efficacy regarding pain. Those receiving benzodiazepines in the
context of pain management were more likely to be prescribed higher-risk opioid
doses (>200 mg morphine equivalents per day) and to be using antidepressant or
antipsychotic medications. These patients were also more likely to have an
alcohol use disorder, to use illicit substances and had greater mental health
comorbidity. Further, those taking opioids concomitantly with benzodiazepines
had greater past month use of emergency health care and were more likely to
experience an overdose event (67).
In summary, benzodiazepines are frequently utilized in pain management.
Addiction to benzodiazepines used in pain management appears to be
uncommon. However, evidence for benefit of benzodiazepines in acute pain
management is small, and there is no evidence for the benefit of benzodiazepines
in pain management when used chronically. There is evidence for harm
associated with benzodiazepine use in pain treatment including drug–drug
interactions particularly with opioid analgesics, impairment and accidents, and
rebound anxiety related to withdrawal as chronicity of use increases. The weak
evidence for benefit of benzodiazepines versus risk of serious adverse events in
the setting of pain management should be carefully considered by prescribing
clinicians. As with the increasing understanding of the lack of evidence for the
use of opioid therapies for chronic pain (75) and guidance to avoid opioids as a
first-line therapy, the same should apply to benzodiazepine use in pain
management.
MECHANISM OF TOLERANCE AND

WITHDRAWAL
The pharmacodynamic mechanisms underlying the development of tolerance
and withdrawal to sedative hypnotics have been extensively studied. Tolerance,
as evidenced by decreased responsiveness of GABAA receptors to
benzodiazepines, has been demonstrated using measures of both
electrophysiological activity (76,77) and GABA-mediated chloride flux (78).
The decreased ability of benzodiazepines to positively modulate GABAA
receptors may result, in part, from the loss of interaction between
benzodiazepine and GABA-binding sites within these receptors, referred to as
“uncoupling” (79,80). Zolpidem may also produce uncoupling between these
binding sites (81). Another possible mechanism of tolerance may involve
benzodiazepine-induced internalization of surface GABAA receptors into
intraneuronal sequestration sites (80). In vitro studies indicate that levels of the
messenger RNAs (mRNAs) that are involved in the synthesis of the α1 GABAA
receptor subunit are reduced during prolonged exposure to benzodiazepines,
whereas mRNAs for the benzodiazepine-insensitive α4 subunit are increased
soon after benzodiazepine withdrawal (82). These changes in α4 subunit
expression correlate with decreased sensitivity to the effects of benzodiazepines
on GABA-mediated chloride currents (83). This loss of sensitivity can be
prevented by blockade of the expression of α4 subunits. These findings point to
the possible role of increased α4 subunit expression in early benzodiazepine
withdrawal.
The glutamatergic system may play a major role in the benzodiazepine
withdrawal syndrome. In animal models, anxiety associated with benzodiazepine
withdrawal may involve up-regulation of hippocampal AMPA receptors as
evidenced by increased AMPA receptor GluR1 subunits and increased AMPA
receptor binding (84–87). Other studies have confirmed increased AMPA
receptor binding in the hippocampus and thalamus using different experimental
paradigms of withdrawal, but have not found corresponding alterations in levels
of the GluR1 or GluR2 subunits in these brain regions (88). AMPA-mediated
conductance in hippocampal neurons has been shown to be enhanced by abrupt
withdrawal from benzodiazepines (89). These changes occur in association with
the presence of anxiety-related behaviors.
ADDICTION LIABILITY
The benzodiazepines occupy an intermediate position of addiction liability, and
nonbenzodiazepines have lower potential for addiction, although both classes of
medications are controlled substances. Benzodiazepines, depending on
assessment of addiction liability, have been placed on schedules IV and V (the
lower the schedule number, the greater the risk for unhealthy use of a
medication), and nonbenzodiazepines have been placed on schedule V. More
controversial is the issue of relative addiction liability among the
benzodiazepines themselves. Using the sole criterion of a euphoric mood
(positive reinforcement) effect in humans, the benzodiazepines with the highest
liability for addiction are flunitrazepam, diazepam, alprazolam, and possibly
lorazepam. Those with the lowest positive reinforcing effects in humans are
clonazepam, chlordiazepoxide, halazepam (43), prazepam (90), quazepam, and
oxazepam. However, individuals at risk for sedative–hypnotic addiction (eg,
those with an alcohol use disorder) may misuse any of the benzodiazepines, even
those with relatively low potential for addiction. Benzodiazepines with the
highest addiction potential are those that produce a rapid onset of pleasant mood,
well-being, relief of dysphoria and anxiety, and a general state of contentment
(91).
The relative addiction liability of nonbenzodiazepines, compared to
benzodiazepines, is a matter of some controversy. While the nonbenzodiazepines
were initially thought to have little addiction liability, human laboratory studies
have shown that zolpidem administration increases subjective responses such as
“drug liking” and “good effects” in both people who use substances (92) and
healthy volunteers (93) indicating addiction potential. In other human laboratory
studies that assessed addiction potential, these drugs produce euphoric effects at
doses above their typical therapeutic ranges. For example, eszopiclone, at doses
of 6 and 12 mg, produced euphoric effects comparable to 20 mg of diazepam in
people who previously used sedative–hypnotics. Studies examining the addiction
liability of 25, 50, and 75 mg of zaleplon in subjects with a history of sedative–
hypnotic addiction, indicated addiction potential similar to benzodiazepines and
benzodiazepine-like hypnotics.
EPIDEMIOLOGY OF UNHEALTHY USE

Benzodiazepines including alprazolam, clonazepam, and lorazepam remain
some of the most commonly prescribed psychiatric medications, with
approximately 47.8 million prescriptions written for alprazolam, the most
frequently prescribed benzodiazepine, in 2011 (94). Benzodiazepine use and
unhealthy use has been increasing for a number of years. From 2004 to 2011,
significant increases in the numbers of overdoses and deaths involving
benzodiazepines have been observed. In 2012, benzodiazepines were involved in
28.7% of emergency department visits related to drug toxicities, with alprazolam
indicated in about a third of such visits (66). Data from the National Survey on
Drug Use and Health (2013) estimated that there were 1.7 million people who
engaged in nonmedical use of tranquilizers and sedatives (mainly
benzodiazepines) in the United States (95).
There are certain groups of high-risk patients where long-term use,
unhealthy use, and addiction are greater than in patients with anxiety disorders.
Individuals with a history of alcohol use disorder comprise one group of
individuals with higher rates of benzodiazepine-related problems.
Approximately 15%-20% of people with an alcohol use disorder presenting for
treatment may be using benzodiazepines in an unhealthy manner (1,96,97).
Several groups report positive mood enhancement from acute benzodiazepine
doses, including people who are moderate and heavy drinkers (98,99), people
with alcohol use disorders who are abstinent (37,38,100), and individuals who
have strong family histories of alcoholism (101–103). These findings suggest
that mood elevation may be one of the factors contributing to use of
benzodiazepines in individuals with alcohol use disorder and possibly in those
with a family history of alcoholism.
Another group of individuals in whom unhealthy benzodiazepine use is
particularly high in both the United States and Europe are those with a history of
opioid use. This includes both individuals who are using opioids in an unhealthy
manner and those who are receiving opioid therapy for opioid use disorder (62).
The most common reason such individuals use benzodiazepines is to manage
anxiety and opioid withdrawal. Benzodiazepine use has also been reported to
enhance euphoria or “high” when ingested concomitantly with opioids thereby
increasing the risk of coadministration (104). In opioid treatment programs
(which provide either methadone or buprenorphine pharmacotherapy for opioid
use disorder), urine toxicology that tests positive for benzodiazepines is
common. In one report, 47% of patients in a methadone maintenance program
reported having a history of benzodiazepine use, with more than half of these
patients starting the use of benzodiazepines after entering the methadone
maintenance program (105). Rates of concurrent benzodiazepine use are also
high for individuals receiving buprenorphine/naloxone treatment for opioid use
disorder (106,107). These issues cause concern for risk of overdose.
TOXICITIES
It is well established that acute doses of benzodiazepines can be associated with
adverse effects that include anterograde amnesia, difficulty acquiring new
learning (108), and sedation that may affect attention and concentration.
Tolerance usually develops to most of the cognitive effects, but not in all
patients. Those who use intermittent doses (such as “as needed” dosing) of high-
potency agents may not develop tolerance and continue to be at risk for impaired
psychomotor and memory functions, especially in the first few hours after taking
a dose. Furthermore, studies (109) and clinical experience suggest that not all
benzodiazepines produce the same type or severity of cognitive impairment.
Although some studies have found no cognitive impairment associated with
long-term benzodiazepine treatment (110,111), others have reported persistent
problems in psychomotor function, learning, concentration, and visuospatial
skills (112,113). In people who chronicly used benzodiazepines, greater
impairment is seen in men, elderly, and individuals taking the highest doses
(108). A meta-analysis suggested pervasive cognitive impairment in people who
chronically used them, but the interpretation is complicated by comparing
studies with different methods and populations (112). Long-term cognitive
impairment was observed in concentration, general intelligence, problem-
solving, and psychomotor speed at 3 months following cessation of
benzodiazepines (110). Further, these patients still perform worse than controls
at 6 months after the medication is stopped (114).
Benzodiazepines are widely prescribed in the elderly, despite the known
risks in older people (eg, impaired cognition and mobility as well as increased
risk of falls and associated injuries). An association between benzodiazepine use
in older people and increased risk of Alzheimer disease has also been described
(115), though one study found the memory impairment in elderly taking
benzodiazepines to be small (116). Falls, however, present a serious risk to the
elderly. Classic benzodiazepines, nonbenzodiazepine hypnotics, SSRI
antidepressants, and antipsychotics have all been linked to falls and fractures in
the elderly (117–119), underscoring the need to consider the risk/benefit ratio of
such medications in this population.
Zolpidem also produces anterograde amnesia and has been associated with
somnambulism and complex nocturnal behaviors, such as eating, shopping, and
driving. Similar problems may be seen with zaleplon, especially at high doses. It
is not known whether all hypnotics are capable of producing such effects;
however, the FDA has required a label change for benzodiazepine and
nonbenzodiazepine hypnotics to include a warning describing these complex
sleep-related behaviors.
Several surveys in different countries have found a higher incidence of
motor vehicle accidents associated with benzodiazepines (120,121). It is not
known whether this reflects acute psychomotor impairment, somnolence, or
persistent visuospatial impairment. Zolpidem at a high (20 mg) dose when
administered in the middle of the night can produce decrements in driving
performance the following morning (122).
The risks of benzodiazepines during pregnancy and lactation have been the
subject of controversy. Data pooled from cohort studies have not demonstrated
an increased risk of major malformations or cleft palate (123). Conversely, when
data from case control studies were pooled in the same meta-analysis, a small
but statistically significant association was found between exposure to
benzodiazepines and oral cleft abnormalities or other major malformations. The
rate of cleft palate in the general population is estimated at 0.06% (124), and
case–control studies show that with benzodiazepines the risk may be
approximately doubled at 0.12%.
In a well-designed study of 873,879 infants whose mothers were registered
in the Swedish Medical Birth Register, 1979 infants were exposed to
benzodiazepines or nonbenzodiazepine hypnotics (mainly zopiclone), but
increased risk of orofacial clefts was not found (125). An increased risk for low
birth weight in infants that had both early and late exposure to benzodiazepines
in utero was reported, but it was most evident in women who also had been
taking an antidepressant. They also found an unexpectedly high number of
infants with pylorostenosis and alimentary tract atresia, although concomitant
exposure to antidepressants and an anticonvulsant complicates the interpretation
of the finding. Another study found that infants exposed in the first trimester to
the combination of serotonin reuptake inhibitor antidepressants and
benzodiazepines had increased risk of congenital anomalies and congenital heart
disease compared to unexposed; however, when maternal illness was controlled,
only the increased risk for congenital heart disease remained significant (126).
Monotherapy with either class of drug was not associated with an increased risk.
Most recent studies have not found an association of in utero benzodiazepine
exposure alone with major congenital anomalies (127,128).
Although the major concern of clinicians has been congenital anomalies
associated with benzodiazepines, two other clinically important problems may
be encountered during pregnancy. Newborns who have been exposed to
benzodiazepines in utero during third last trimester or during delivery may
present with floppy baby syndrome. This condition is characterized by low
Apgar scores, poor sucking, hypotonia, poor reflexes, and apnea (129). Neonatal
withdrawal syndromes have also been reported (130).
Benzodiazepines administered to nursing mothers enter the breast milk but
appear in such low concentrations that they do not usually cause adverse effects
in infants (131–134). There are two important exceptions to this general rule: the
risk to the infant is higher (a) if the benzodiazepine is given in high doses
antepartum and continued postpartum and (b) if infants have impaired hepatic
function, as evidenced by hyperbilirubinemia (133). Despite their relative safety,
breastfed infants whose mothers are taking benzodiazepines should be monitored
for lethargy, weight loss, and signs of an abstinence syndrome.
In summary, benzodiazepines and nonbenzodiazepines can present a risk for
significant adverse events associated with their use both acutely and chronically.
These medications are widely prescribed for anxiety, for insomnia, and in pain
management. Tolerance rapidly develops over weeks to months for anxiolytic
and sleep-producing effects. Therefore, while acute or short-term administration
of these medications can be useful, chronic use should generally be discouraged
as a primary means of avoiding the toxicities that have been reported.
MEDICAL COMPLICATIONS
The principal medical complications with benzodiazepines are related to
overdose and withdrawal syndromes. All sedative/hypnotics produce effects on a
continuum from sedation to obtundation. In overdose situations, sedative
hypnotics are often combined with ethanol or other CNS depressants. When high
doses of benzodiazepines are ingested, either as a therapeutic intervention or in
an overdose, initial signs of toxicity are ataxia and impaired gag reflex as well as
CNS depression. Respiratory depression may also occur in overdose, and the
medical approach to overdose treatment is supportive care. Rarely, medical
complications of sedative hypnotic use can include disinhibition or paradoxical
excitement.
A severe withdrawal syndrome after high-dose chronic administration of
chlordiazepoxide or diazepam was demonstrated in the early 1960s (135,136)
and, in its most severe form, can include grand mal seizures and psychosis. A
characteristic abstinence syndrome may develop upon abrupt discontinuation of
therapeutic doses of benzodiazepines that are administered for several weeks
(137). When administered for short periods and at therapeutic doses, the
withdrawal syndrome is usually mild, consisting of anxiety, headache, insomnia,
dysphoria, tremor, and muscle twitching. After long-term treatment with
therapeutic doses, the syndrome increases in severity and may include
autonomic dysfunction, nausea, vomiting, depersonalization, derealization,
delirium, hallucinations, illusions, agitation, and grand mal seizures. The time
course of the withdrawal syndrome is related to the half-life of the agent, with
patients taking short half-life agents (lorazepam, alprazolam, temazepam)
developing symptoms within 24 hours of discontinuation, the severity of which
peaks at 48 hours. With longer half-life agents such as diazepam, symptoms may
develop a week after drug discontinuation and last for several weeks. This
timeline should be used as a general guideline, because some patients on long-
acting agents will develop symptoms earlier than predicted by the
pharmacokinetics of the drug. In addition, some clinicians believe that there is a
prolonged withdrawal syndrome that persists for several months, but it has not
been clearly distinguished from return of original anxiety symptoms. Longer
duration of treatment with benzodiazepines and/or the administration of higher
doses of these agents increases the odds for the development of physical
dependence and, potentially, development of a substance use disorder (138).
In general, longer treatment periods, higher doses, sudden drug
discontinuation, and psychopathology increase the severity of the withdrawal
syndrome. Clinical experience has shown that there is great variability in the
sensitivity of patients to discontinuation of benzodiazepines. All patients who
have been taking a benzodiazepine for several weeks or longer should have the
medication tapered to avoid withdrawal and safely discontinue use.
CONCLUSION
Among drugs within the sedative-hypnotic class, benzodiazepines are the most
widely prescribed by providers, and the most widey used in unhealthy ways. In
animal models and human laboratory studies, they occupy a lesser position of
addiction liability relative to opioids and some stimulant medications as
indicated by their placement in schedules IV and V. In patients with anxiety
disorders, unhealthy use is not common; however, certain subgroups of patients,
such as individuals with alcohol use disorder and those receiving opioid
therapies for opioid use disorder, are at higher risk for unhealthy use. Compared
to the general population, higher rates of benzodiazepine use are found in the
elderly and in patients with chronic pain. And the higher use is accompanied by
significant risks for adverse events and overdose deaths, particularly when taken
in combination with opioid medications. The newer nonbenzodiazepine
hypnotics may have a lower potential for tolerance or even the development of a
substance use disorder, though they are not devoid of such risk. The
identification of GABAA receptor subtypes and clarification of their function
provide hope that drug development will lead to GABAA agonists and
modulators that have fewer adverse effects, lower risk for addiction, and greater
specificity of action (139).
NONALCOHOL SEDATIVE HYPNOTIC

PATIENT CASE
Ms. A. was a 42-year-old woman with a history of low back pain for which she
had been treated with chronic opioid therapy (COT) for the last 3 years. She
had been initially treated with hydrocodone 5 mg thrice daily, but over the
ensuing years, her pain worsened and her COT had been changed and increased
to extended-release oxycodone 40 mg thrice daily. On that regimen, her low
back pain was under control, but she reported recent onset of anxiety and
experienced frequent insomnia. Her physician prescribed lorazepam 1 mg
thrice daily as needed and 1 mg at bedtime, which could be repeated if
necessary during the night. The patient began taking a total of lorazepam 5 mg
daily and on the 3rd day was found unresponsive and not breathing. She was
immediately given airway support, and intravenous naloxone 2 mg was
administered at the scene by emergency medical personnel. She began to
breathe on her own again, regained consciousness, and was evaluated and
further stabilized in the emergency department. In considering the patient’s
response to the prescribed opioid and benzodiazepine medications, it is most
likely that she experienced a pharmacodynamic drug–drug interaction in which
the synergistic effect of opioids in combination with benzodiazepines together
produced respiratory depression and the unresponsive state.
This patient will need reassessment of her COT, as evidence of benefit for
low back pain remains limited, while risks are well known, especially when
combined with other CNS depressants. Other approaches to treatment of low
back pain will need to be considered including physical therapy, exercise, and
other alternative therapies. Benzodiazepines are not the first-line treatment for
anxiety; rather medication management includes selective serotonin reuptake
inhibitors and psychotherapeutic intervention. Sleep management techniques
should be offered and benzodiazepines should be avoided. Nonbenzodiazepine
hypnotic medications for insomnia should be kept to short-term use (eg, 2-4
weeks) as tolerance can rapidly develop and additional risks remain.
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CHAPTER 11
The Pharmacology of Opioids
Daryl Shorter and Thomas R. Kosten
CHAPTER OUTLINE
Definition of Drugs in the Class
Substances Included in the Class
Epidemiology of Opioid Use Disorder
Pharmacokinetics of Specific Drugs
Pharmacodynamics
Tolerance Development
Toxicity States and their Medical Management
Medical Complications of Opioids
Conclusions and Future Research Directions
DEFINITION OF DRUGS IN THE CLASS

Three distinct types of opioid receptors are found in the nervous system: mu,
kappa, and delta. These opioid receptors are G-protein–coupled, 7-
transmembrane receptors. The endogenous opioid neuropeptide agonists include
the endorphins, enkephalins, and dynorphins as well as the more recently
characterized endomorphins (1,2). The endorphins are cleavage products of the
protein, pro-opiomelanocortin (POMC), which is produced primarily in the
anterior pituitary of humans by the POMC gene. The major endorphin agonist
produced from POMC is beta-endorphin, while the shorter products, alpha-
endorphin and gamma-endorphin, are less biologically active peptides (3). Beta-
endorphin stimulates mu opioid receptors (MOP-r) in mediating both the
analgesic and rewarding effects of opioids. The enkephalins and dynorphins are
opioid peptides with affinity for MOP-r as well, but enkephalins are primarily
active at delta opioid receptors, while dynorphins exert their activity primarily
through kappa opioid receptors (1). The endomorphins, endomorphin-1 and
endomorphin-2, are opioid tetrapeptides with high affinity and selectivity for
MOP-r. Although the parent gene and precursor protein of the endomorphins are
still yet to be characterized, these agents may represent an important advance in
development of opioid medications due to their potent antinociception and
reduced adverse effects in rodent models (4).
Opium is a naturally occurring mixture directly derived from the juice of the
opium poppy (Papaver somniferum). Opioid analgesic medications are agonists
at MOP-r. Morphine (the prototypical MOP-r agonist) is the main active alkaloid
in opium and constitutes roughly 10% (by weight), while codeine and thebaine
are also present, but in much lower concentrations. Codeine is used medicinally
as an analgesic and antitussive, whereas thebaine can be used as a starting point
for producing semisynthetic MOP-r ligands. Several exogenous opioids are
significant for opioid use disorder: heroin, morphine, oxycodone, codeine,
meperidine, pentazocine, hydromorphone, and hydrocodone, as well as
methadone, levo-alpha-acetylmethadol (LAAM), and buprenorphine.
SUBSTANCES INCLUDED IN THE CLASS
Naturally Occurring Agents

Morphine
Morphine is a natural product of the poppy plant, Papaver somniferum. Its use
dates back to the early 19th century, following the publication of a method for its
isolation in 1817 (5). Today, morphine treats moderate to severe pain and is used
orally, intravenously, intramuscularly, or intrathecally. Mammalian cells can also
endogenously synthesize morphine (6).
Codeine
Codeine is methylmorphine, and crosses the blood–brain barrier faster and has
less first-pass metabolism in the liver for greater oral bioavailability than
morphine. It also is metabolized to morphine via cytochrome 2D6 (4) and to
hydrocodone by an unknown mechanism (7).
Thebaine and Synthetic Compounds

Thebaine is not used clinically or recreationally, but is a potent convulsant and
the chemical basis for several semisynthetic opioids. Modifications of thebaine
results in hydrocodone (Vicodin), oxycodone (OxyContin), hydromorphone
(Dilaudid), and heroin. Synthetic modifications also include antagonists such as
naloxone (Narcan), naltrexone (Trexan or ReVia or Vivitrol), and nalmefene
(Revex), as well as partial agonists such as buprenorphine alone (Subutex) or,
when combined with naloxone, (Suboxone, Zubsolv) (4).
Synthetic Agents
Heroin
Heroin is derived from morphine, and its rapid onset of action and short half-life
make it preferred over morphine among people who engage in unhealthy opioid
use. Heroin is in Schedule I (ie, not available for any therapeutic use in the
United States), although a few select countries (eg, Switzerland, the Netherlands,
Spain, Germany, Canada, and the United Kingdom) use it as a medication for
treatment of intravenous heroin use disorder. In these countries heroin is used
only in patients who have not responded to methadone or buprenorphine
maintenance treatment or residential rehabilitation (8–10). A prodrug that is not
itself active, heroin is rapidly deacetylated to 6-monoacetyl morphine (6-MAM)
and morphine, both of which are active at the MOP-r. It is most effective
intravenously but increasingly is used intranasally and, sometimes, smoked (11),
which is possible with high-purity heroin. Nasal and smoked use also reduces
the risk of human immunodeficiency virus (HIV-1) transmission and overdose
(12).
Oxycodone
Although oxycodone is structurally similar to codeine, it is
pharmacodynamically comparable to morphine with a 1:2 equivalence to
morphine (13). It is combined with aspirin or acetaminophen for treating
moderate pain and is available orally without a coanalgesic for severe pain (14).
By the mid-2000s, oxycodone had become one of the most widely misused and
diverted opioids in the United States, particularly in the controlled-release (CR)
formulation, since it could be easily crushed and self-administered (intranasally
or IV) for a potentially toxic, rapid “high” (15,16). Subsequently, in 2010, the
medication was reformulated and released in a tamper-resistant, unhealthy use-
deterrent form characterized by reduced euphoria, nasal irritation with
insufflation, and difficulty with extraction of the active compound (17).
Following reformulation, oxycodone misuse dropped, but heroin use rose.
Meperidine
Meperidine is a phenylpiperidine with limited potency and a short duration of
action. Clinically, meperidine is used primarily for the management of acute,
postoperative pain in the central nervous system (CNS) and gastrointestinal and
genitourinary systems, and prophylactic use of meperidine has been shown to
reduce postoperative shivering, particularly for patients undergoing spinal
anesthesia (18). Meperidine is no longer used for treatment of chronic pain
owing largely to concerns regarding toxicity of its major metabolite,
normeperidine, which can produce seizures and CNS excitation, for example,
disorientation, drowsiness, vertigo, or urinary retention (19). While meperidine
is metabolized primarily by the liver, normeperidine is renally excreted, has a
substantially longer half-life (15-30 hours), and carries a risk of accumulation in
those with renal disease and the elderly (20). Meperidine should not be used for
>48 hours or at doses >600 mg/d. Because it has serotonergic activity, it can
produce a serotonin syndrome (ie, clonus, hyperreflexia, hyperthermia, and
agitation) when combined with monoamine oxidase inhibitors (21). Additionally,
meperidine use has been associated with electrocardiogram (ECG) changes, such
as QTc prolongation, which can lead to torsade de pointes, a potentially fatal
arrhythmia (22).
Pentazocine
Pentazocine treats moderate to severe pain but is a weak antagonist or partial
agonist (ie, it has a “ceiling effect,” plateau in maximal effect, contrasted with a
full agonist) at the mu receptor. It is also a kappa receptor partial agonist and
displays activity at the delta opioid receptor as well as the sigma receptor.
Pentazocine shows differences in CNS effect and degree of analgesia depending
upon the medication dose. In addition, pentazocine has two enantiomers with
different pharmacological profiles, and the prescribed formulation, (±)-
pentazocine, provides pain reduction and is rewarding. In rats, (−)-pentazocine is
rewarding through mu and delta opioid receptors, while (+)-pentazocine is not
rewarding through agonism of the selective sigma-1 receptor, which also
underlies its hallucinogenic and psychotomimetic properties (23). In 1983, as a
deterrent to unhealthy use, pentazocine was manufactured in combination with
naloxone (Talwin NX). Thus, if injected, this formulation would actually
precipitate withdrawal in those with physiological dependence. After this
change, unhealthy use of pentazocine in the United States has declined.
Hydromorphone
First synthesized in the 1920s, hydromorphone is a more potent opioid analgesic
than morphine. It is used for the treatment of moderate to severe pain and is
excreted, along with its metabolites, by the kidney. It can be given intravenously,
by infusion, orally, and per rectum, with low oral bioavailability. On a milligram
basis, it is five times more potent than morphine when given orally and 8.5 times
as potent when given intravenously (24). A minor pathway for the metabolism of
morphine to hydromorphone has been identified (25).
Hydrocodone
Hydrocodone is a prescription medication for relatively minor pain, such as
oral/dental or osteoarthritis. Hydrocodone undergoes hepatic metabolism entirely
by the CYP2D6 system to its active metabolite, hydromorphone, which is then
further converted by phase 2 glucuronidation (26). When used in combination
with acetaminophen, there can be an increased risk of hepatotoxicity when used
in unhealthy ways (14).
The amount of hydrocodone used in the United States has increased
substantially. In 1990, the world’s population consumed 4 tons (3628 kg) of
hydrocodone, and by 2009, annual worldwide consumption of hydrocodone had
risen to 39 tons (35 380 kg), with 99% of that amount being consumed by
Americans. Of note, a substantial portion of this is consumed for nonmedical use
(27). As a result, in October 2014, the Drug Enforcement Agency (DEA)
rescheduled hydrocodone from Schedule III to Schedule II, in large part due to
its high potential for unhealthy use. Subsequently, in the year following the
change, hydrocodone prescriptions decreased by 22%, from ~120 to 93.5
million.
Methadone
Methadone is a synthetic long-acting full mu opioid agonist, active by parenteral
and oral routes. It was first synthesized as a potential analgesic in Germany in
the late 1930s and first studied for human use in the 1950s in the United States.
It has been used primarily as a maintenance treatment for heroin use disorder
since the first research done in 1964 (28), and it was approved by the U.S. Food
and Drug Administration (FDA) in 1972. Methadone is also effective in the
treatment of chronic pain; however, it should be used with caution in opioid-
naïve patients due to the risk of accumulation and respiratory depression.
Methadone has a diphenylheptylamine chemical structure and consists of a
racemic mixture of D(S)- and L(R)-methadone (29). The L(R)-methadone
enantiomer has up to 50 times more analgesic activity and also the potential to
produce more respiratory depression than the D(S)-enantiomer. Both enantiomers
have modest N-methyl-D-aspartate (NMDA) receptor antagonism, which is
thought to be the underlying neurobiological mechanism for the limited
development of tolerance observed with this medication (30,31).
Levo-alpha-acetylmethadol
LAAM is a synthetic, longer-acting (48-hour) congener of methadone that is also
orally administered. LAAM was first studied in the 1970s for the treatment of
heroin use disorder (32) and approved in 1993 by the FDA (33) after a large
multicenter safety trial. A black box warning was added to the product label due
to postmarketing reports of prolonged QTc interval on ECG that were associated
with treatment with LAAM (34,35). Although LAAM remains approved for
human use in the United States, no pharmaceutical company is manufacturing
the medication at this time. As the new drug application for LAAM has not been
withdrawn, LAAM could once again be made available in the United States (36).
Buprenorphine
Buprenorphine alone, and in combination with opioid antagonist, naloxone, was
approved in 2002 by the FDA as an office-based treatment for heroin and opioid
use disorder (37,38); at the same time, buprenorphine was reclassified by the
Drug Enforcement Administration from a Schedule V to a Schedule III drug
(39). Buprenorphine is primarily a MOP-r–directed partial agonist, but also acts
as a kappa partial agonist. The structure of buprenorphine is that of an oripavine
with a C7 side chain, which contains a tert-butyl group. Norbuprenorphine is a
major metabolite of buprenorphine in humans, with activity at the MOP-r as well
(40).
The SAMHSA DATA 2000 (Drug Addiction Treatment Act 2000)
established eligibility requirements for physicians to use buprenorphine in the
office-based treatment of opioid use disorders. Prescribers must complete an 8-
hour continuing medical education course and notify the government of their
intent to use buprenorphine for treatment of patients with opioid use disorder by
obtaining a waiver from the DEA. Additionally, prescribers must have both the
capacity to provide or refer patients for ancillary services. When originally
proposed, the number of patients who could be provided treatment from a single
prescriber at any one time in an individual or group practice was no more than
30; as of 2016, the limit on the number of patients was raised to 275 (41,42). As
well, Nurse Practitioners and Physician Assistants are now able to prescribe this
medication.
The formulations of specific drugs are shown in Table 11-1.
TABLE 11-1 Formulations and Their Methods of

Use/Unhealthy Use
Formulations to Deter Unhealthy Use
Formulations are being developed for many opioids to deter unhealthy use. The
addition of an opioid antagonist, such as naloxone or naltrexone, to the parent
opioid compound is a common pharmacological strategy, employed with
medications including pentazocine/naloxone (Talwin NX) and
buprenorphine/naloxone. Other formulations are designed with physical
deterrents to intranasal or parenteral use and include adding capsaicin or a
gelling polymer to make dissolved pills unpleasant to use due to nasal irritation
or difficult to crush or dissolve due to structurally resistant, tamper-proof outside
coatings (43).
Clinical Uses
Clinically used opioids (ie, MOP-r agonists) are indicated primarily for
treatment of acute and chronic pain conditions. For minor pain, such as
postdental procedures, opioids such as hydrocodone are used. For moderate to
severe, postsurgical, or chronic pain, opioids such as morphine may be
prescribed. Neuropathic or regional pain syndromes can sometimes be relieved
by opioids, though their prolonged use in these conditions remains an area of
continued investigation. Opioids have been well established as cough
suppressants; however, only codeine is typically used for this indication.
Although the mechanism of action is not entirely clear and more research into
this indication is needed (44), low-dose opioids have also been found to improve
refractory breathlessness in terminal illnesses, such as end-stage chronic
obstructive pulmonary disease (COPD).
The opioid agonists, methadone and buprenorphine, are employed as
treatment for opioid use disorder; with the latter two used for either withdrawal
management to reduce withdrawal symptoms or maintenance therapy (to reduce
craving and re-establish physiological homeostasis). All opioid medications
carry the risk for development of substance use disorder and diversion, and as a
result, they must be dispensed cautiously. This caution, however, must be
carefully balanced against the risk of undermedicating pain for each individual
patient. Depot naltrexone (Vivitrol) was approved in 2010 as a monthly IM
injection for prevention of relapse following withdrawal management from
opioid use disorder. An implantable version of buprenorphine is also recently
approved with at least two other depot forms of buprenorphine pending FDA
approval for monthly use (45).
Nonmedical Use of Prescription Medications (NUPM)
Recreational or illicit use of opioids may initiate from a desire to experience the
euphorigenic effects of these agents. There are also those who favor use of
prescription medications because they are not associated with the societal stigma
of heroin or the negative consequences of IV drug use. Additionally, some
patients are prescribed opioids for pain treatment and go on to develop unhealthy
opioid use. Heroin, as mentioned, is not available for medical indications in the
United States. Methadone and buprenorphine are sometimes diverted by those
for whom it is prescribed, generally not for euphoria-inducing effects, but rather
to prevent the onset of opioid withdrawal symptoms (46).
Historical Features
Sumerian clay tablets (3000 BC) refer to the poppy; Sumerians named opium
“gil” (“happiness”). The ancient Egyptians also cultivated poppies. “Thebaine”
is derived from the name for the Egyptian city “Thebes.” “Opium” may be a
Greek-derived word (“opion” = poppy juice). Opium figures prominently in
Greek mythology and was also mentioned in Hippocrates’ writings (460-377 BC).
The ancient Roman author Pliny warned of the dangers of compulsive use of
opium. In 1804, a young German pharmacist, Friedrich Sertürner, isolated
morphine (which he named after Morpheus, the Greek god of dreams) (47). A
major development in the delivery of opioids, the hypodermic needle was
perfected in 1853, which allowed for rapid analgesia, but also greater morbidity
and mortality when misused. Diacetylmorphine was first synthesized as a
semisynthetic analog in the 1870s by the Bayer company and marketed under the
name “heroin.”
EPIDEMIOLOGY OF OPIOID USE

DISORDER
The pharmacology of opioids is of particular relevance to the treatment of
substance use disorder, given recent increases in the use of illicit opioids, as well
as nonmedical use of prescribed opioid medications (48). According to the 2014
National Survey on Drug Use and Health (NSDUH), there were an estimated 4.3
million people currently (ie, past month) nonmedically using prescription
opioids and 914,000 people who used heroin in the past year. By extension, an
estimated 1.9 million persons (aged 12 or older) met the Diagnostic and
Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for
diagnosis of opioid use disorder related to prescription opioids, and ~586,000
met criteria for heroin use disorder. Regarding adolescent use, in 2014, an
estimated 467,000 persons aged 12-17 years old were currently using
nonmedical pain relievers, and 168,000 adolescents met criteria for opioid use
disorder related to prescription opioids. Importantly, these estimates for
adolescent use represent a near-continuous decline over the last several years and
are supported by other epidemiological studies, including Monitoring the Future,
which found that use of “narcotics other than heroin” in 12th graders peaked at
4.3% of respondents in 2004, but had declined to a rate of 1.7% in 2016 (49).
Less than 1% of students in 8th, 10th, and 12th grades reported current use of
heroin in 2014.
Interesting differences occur in the nonmedical use of prescription opioids
on the basis of racial/ethnic group identification. For example, a study of 18- to
23-year-old adults who used opioids nonmedically but who had not yet met
criteria for opioid use disorder/dependence found that a higher proportion of
white adults who used opioids for euphoria, used opioids orally or by snorting.
In contrast, non-white adultstended to use oral opioids to self-medicate health
problems (50). Additionally, in a separate study in college students, researchers
found recreational use was more prevalent among white people who use opioids,
while self-treatment of pain was more prevalent among African Americans (51).
Recent studies examining racial bias in pain assessment and treatment further
suggest that the undermedication of pain among certain groups is related to false
beliefs and misperceptions about physiological differences between whites and
people of color regarding pain tolerance (52). Altogether, these factors may
contribute to the differing manifestations of nonmedical use of prescription
opioids among diverse populations and represents an important area of future
study, particularly as it is related to potential opportunities for targeted
intervention.
The medical implications of unhealthy opioid use and diversion are quite
significant. Family members and friends are the most common source of
nonmedically used opioids; however, family members and friends most
commonly receive those medications directly from physicians. Prescribing
practices related to opioids are not the sole clinical concern. Benzodiazepines
and opioid pain medications are commonly used in combination, and recent
guidelines from the CDC clarify the dangers of concomitant use and caution
against it, given the elevated risk of respiratory depression, coma, and death
(53). Additionally, opioid-related overdoses have become an area of significant
concern, particularly since counterfeit medications have flooded the illicit
market and may be adulterated with agents that contribute significantly to
toxicity. According to the National Center for Health Statistics, the number of
drug poisoning deaths involving natural and semisynthetic opioids increased
each year from 2749 deaths in 1999 to 11 693 deaths in 2007, while the number
of deaths involving synthetic opioids other than methadone (ie, fentanyl,
meperidine, and propoxyphene) increased from 730 deaths in 1999 to 2666
deaths in 2011 (54). Interestingly, the number of methadone-related deaths
increased from 784 deaths in 1999 to 5518 deaths in 2005, but since that time,
methadone-related deaths have declined, accounting for 4418 deaths in 2011. Of
note, benzodiazepines were also involved in 31% of opioid analgesic deaths in
2011. Also, the number of opioid-related deaths among non-Hispanic blacks
more than doubled between 1999 and 2011, while the number of deaths among
non-Hispanic whites more than quadrupled.
According to the Substance Abuse and Mental Health Services
Administration (SAMHSA) Treatment Episode Data Set (TEDS), annual
admissions to substance use disorder treatment for primary heroin use disorder
increased from 228,000 in 1995 to ~256,000 in 2010, with the percentage of
primary heroin admissions remaining steady at about 14%-15% of all treatment
admissions (55). At that time, 30.1% of persons with heroin use disorder sought
treatment with methadone or buprenorphine maintenance, whereas only 19.9%
of those with prescription opioid use disorder sought such pharmacotherapy.
However, as the rates of prescription opioid use disorder has increased, there has
been a subsequent increase in treatment seeking. According to TEDS, the annual
number of admissions for other opiates/synthetics increased from 28 316 in 2000
to 157 171 in 2010, growing from 1.6% of all admissions in 2000 to 8.6% of all
admissions in 2010. Likewise, studies historically found that heroin was the
most frequently reported drug of choice in new treatment admissions. However,
a multistate survey of methadone maintenance treatment programs (MMTP)
conducted in 2005 revealed that oral prescription opioids accounted for the
majority of cases, with oxycodone (79%), hydrocodone (67%), methadone
(40%), and morphine (29%) as the most common, outpacing admissions for
heroin (56). One-third of those persons using oral medications also reported a
history of intravenously using their primary drug of choice, suggesting that even
among those with physical dependence on oral agents there is a risk for
progression to IV use.
Although concerns regarding access to treatment persist, some improvement
is evident. Currently, according to SAMHSA, there are ~36 100 US physicians
eligible to prescribe buprenorphine as office-based treatment to patients for
treatment of opioid use disorder, an increase of 33% since 2014 (57).
Approximately 67% of those prescribers are certified to treat up to 30 patients,
and 25% are certified to treat up to 100 patients.
Neurobiology, Mechanisms of Action, and

Relationship to Addiction Liability
Opioids have primarily agonist effects at the MOP-r (encoded by the MOP-r
gene [OPRM1]) (58). MOP-r are members of the G-protein–coupled 7-
transmembrane domain superfamily; they are coupled to Gi and Go proteins.
Thus, MOP-r agonists typically acutely result in the downstream inhibition of
adenylyl cyclase with a consequent reduction in the production of cyclic AMP
(cAMP), the opening of potassium channels, the inhibition of calcium channels,
and the activation of mitogen-activated protein kinase (MAPK) (59,60).
Distribution in CNS and Mediation of

Different Functions
MOP-r are widely distributed in both the CNS and peripheral nervous system
(PNS), with the constellation of their psychological and analgesic effects being
mediated primarily in the CNS (61–63). Therapeutically desirable analgesic
effects can be mediated in areas including dorsal spinal cord and thalamus,
whereas undesirable effects are thought to be mediated elsewhere. Respiratory
depression, for example, is thought to be mediated primarily by activity in the
brain stem (64), while gastrointestinal effects, such as constipation (experienced
by as much as 40% of those prescribed opioids), are thought to be mediated
through CNS activity as well as activation of MOP-r in the gastrointestinal tract,
submucosa, ileal mucosa, stomach, and proximal colon (65). The classic
rewarding effects of MOP-r agonists are likely mediated to a substantial degree
in ventral and dorsal striatal areas and can depend (although not exclusively)
(66) on downstream activation of the dopaminergic mesocorticolimbic and
nigrostriatal systems (67,68). Symptoms of physiological dependence and
withdrawal from MOP-r agonists, such as autonomic instability (eg, blood
pressure and heart rate elevation), diaphoresis, and anxiety, are thought to stem
from increased noradrenergic activity within the locus coeruleus and related
centers (69,70).
MOP-r Signaling Properties and Addiction
Liability
A major underlying concept in the addiction liability of MOP-r agonists is their
pharmacodynamic efficacy (ie, their relative ability to stimulate downstream
second messenger systems). In general, compounds with progressively greater
efficacy (eg, morphine or fentanyl-like compounds) have greater analgesic
effects but also have greater potential for unhealthy use including addiction than
partial agonists such as buprenorphine (59,71). Furthermore, other downstream
effects of MOP-r agonist exposure are now postulated to be of relevance to the
relative balance of therapeutic and undesirable effects of MOP-r agonists,
including propensity to cause tolerance or potential for unhealthy use. Major
mechanisms of current interest are the relative propensity of compounds to cause
MOP-r desensitization and internalization, potentially related to their ability to
stimulate the β-arrestin signaling pathways (72,73). For example, the main active
heroin metabolite, morphine, results in lesser desensitization and internalization
of receptors, compared to the endogenous neuropeptide ligands, or methadone
(74). Thus, methadone maintenance can be used effectively for extended periods
without the development of further tolerance (or progressively greater
methadone dose requirements) (75). By contrast, heroin (through its primary
metabolite, morphine), or prescription opioids, may result in progressive cycles
of physical dependence and tolerance, secondary to a lesser recruitment of
endogenous MOP-r desensitization/internalization mechanisms (76).
PHARMACOKINETICS OF SPECIFIC
DRUGS
It is beyond the scope of this chapter to provide a comprehensive table of dosing
equivalents. There are a number of excellent reviews on this topic (4,14,77).
Morphine Pharmacokinetics
Morphine is largely selective for MOP-r and most physicians consider it the drug
of choice for the treatment of moderate to severe cancer pain (78). The
pharmacokinetics of morphine and its metabolites vary, depending on the route
of administration. Its favorable safety profile is due in large part to its
pharmacokinetic profile. The oral bioavailability varies, from 35% to 75%, with
a plasma half-life ranging from 2 to 3.5 hours. The half-life is less than the time
course of analgesia, which is 4-6 hours, thus reducing accumulation.
Morphine is biotransformed mainly by hepatic glucuronidation to the major
but inactive metabolite morphine-3-glucuronide (M3G) and the biologically
active M6G compound (79), with prolonged clearance because of enterohepatic
cycling with oral dosing (80). In the setting of chronic liver disease, morphine
oxidation is more affected than is glucuronidation. Use of lower doses or longer
dosing intervals is recommended to minimize the risk of accumulation of
morphine when chronic liver disease is present, particularly with repeated
dosing. At 24 hours, more than 90% of morphine has been excreted in urine.
M6G elimination seems to be closely tied to renal function, so accumulation of
metabolites can occur. With renal compromise, <10% of morphine and its
metabolites are excreted in feces; therefore, morphine should be used with great
caution in patients with renal disease (81,82).
Codeine Pharmacokinetics
Codeine has a high oral–parenteral effect, owing to low first-pass metabolism in
the liver. Metabolites are mostly inactive and excreted in the urine, with about
10% demethylated via CYP2D6 to morphine, which may be primarily
responsible for the analgesic effect of codeine, as codeine itself has very low
affinity for opioid receptors. The majority of codeine (~80%) is conjugated with
glucuronic acid to form codeine-6-glucuronide, which is also believed to
contribute somewhat to the analgesic properties of the medication (83). Genetic
variations in 2D6 impact the effects of codeine, with poor metabolizers
experiencing less analgesia due to reduced conversion to morphine and
potentially reduced addiction liability, while ultrarapid metabolizers (ie, those
carrying a CYP2D6 gene duplication) may have increased side effects, such as
sedation (84). The allelic variants have different frequency in different ethnic
groups and can affect the depth of analgesia. Repeated doses of codeine may
result in the accumulation of the active metabolite M6G in patients with renal
disease.
Heroin (Diacetylmorphine) Pharmacokinetics

Heroin is an efficient prodrug with greater water solubility and potency than
morphine (85). It is synthesized from morphine by acetylation at both the 3 and
6 positions and metabolized in humans to active opioid compounds first by
deacetylation to the active 6-monoacetylmorphine (6-MAM, also known as 6-
acetylmorphine [6-AM]) and then by further deacetylation to morphine (85).
Well-designed studies of heroin pharmacokinetics in humans have been
performed (86–89). Heroin has an average half-life in blood of 3 minutes after
intravenous administration; the half-life of 6-AM in humans appears to be 30
minutes (86).
The use of intranasal, intramuscular, and subcutaneous heroin produces peak
blood levels of heroin or 6-AM within 5 minutes; however, intranasal use has
about half the relative potency of parenteral routes (87). Most of the enzymes
involved in the metabolism of opioids are part of the P450 microsomal enzyme
system, though heroin and morphine are also biotransformed outside this system.
Oxycodone Pharmacokinetics
The onset of action of oxycodone begins 1 hour following oral administration.
Although the immediate-release (IR) formulation of oxycodone has a plasma
half-life of 3-4 hours, the controlled-release (CR) formulation lasts for ~12
hours. Stable plasma levels are achieved within 24 hours. Oral bioavailability
ranges from 60% to 87%, with 45% protein bound. Oxycodone is mostly
metabolized in the liver, with the remainder as well as the metabolites
metabolized in the kidneys. The two main metabolites are oxymorphone, which
is also a potent analgesic, and the weaker analgesic noroxycodone, which is its
major metabolite (13,90). In terms of protein binding and lipophilicity,
oxycodone is similar to morphine, with slightly longer half-life and greater
bioavailability. The cytochrome enzyme CYP2D6 mostly metabolizes
oxycodone, while morphine in humans is primarily glucuronidated (91).
Meperidine Pharmacokinetics
Onset of analgesia begins with the oral route after 15 minutes, with peak in 1-2
hours, which is close to peak level in plasma, with duration of about 1.5-3 hours
(4). It is absorbed by all routes, but intramuscular administration results in a less
reliable peak plasma level after 45 minutes, with wide range of plasma
concentrations. After oral administration, about 50% of meperidine enters
circulation without first-pass metabolism, with peak at 1-2 hours. Meperidine is
mostly metabolized in the liver, with half-life of about 3 hours. Cirrhosis leads to
increased bioavailability and half-life of both meperidine and normeperidine.
Sixty percent of meperidine is protein bound and little is excreted unmetabolized
(21).
Pentazocine Pharmacokinetics
Pentazocine is a mixed agonist–antagonist with intermediate activity at both
MOP-r and KOP-r that can be given intramuscularly or orally, but is not
currently available in the oral formulation. It can cause psychotomimetic effects
(likely due to its KOP-r actions) and therefore has a very limited role in the
treatment of chronic pain. Its peak effect is at 0.5-1 hour when given
intramuscularly and 1-2 hours when given orally, and the overall duration of
action is 3-6 hours (14). The drug half-life is 2-3 hours. Sixty percent of the drug
is bound to protein. Pentazocine is metabolized by the liver via oxidative and
glucuronide conjugation with an extensive first-pass effect. When administered
orally, the bioavailability of pentazocine is about 10%, except in patients with
cirrhosis, which increases bioavailability to 60%-70%. Small amounts of
unchanged pentazocine are excreted with urine (14).
Hydromorphone Pharmacokinetics
Hydromorphone is shorter acting than morphine. It is derived from morphine,
although it may also be produced in the body in small amounts by N-
demethylation of hydrocodone. It has an oral bioavailability of 30%-40%, with
an analgesic onset after 10-20 minutes, which peaks at about 30-60 minutes and
persists for about 3-5 hours. The oral–parenteral ratio is about 5:1, with an
equivalency of 1.5 mg of hydrocodone to 10 mg morphine (92).
Hydrocodone Pharmacokinetics
The pharmacokinetics of hydrocodone depends on formulation since there are
commercially available immediate-release (IR) and extended-release (ER)
compounds available. Of note, hydrocodone ER has been reformulated with
unhealthy use-deterrent technology, which limits the release of the active
ingredient in cases of unhealthy use (ie, crushing, snorting) or in combination
with alcohol (93). Hydrocodone IR has a peak effect at 0.5-1 hour and duration
of action of 3-4 hours (14). The half-life of hydrocodone IR is ~3 hours (range:
2-4 hours) (94). Hydrocodone ER has a peak plasma level at roughly 14 hours
(range: 6-30 hours) and analgesic duration of action of ~12 hours, allowing for
twice-daily dosing. The half-life of hydrocodone ER, in comparison, is 6 hours.
Hydrocodone is converted by cytochrome P450 2D6 to its active metabolite,
hydromorphone, and via cytochrome 3A4 to inactive metabolite,
norhydrocodone. Codeine may show up as trace quantities of hydrocodone in
urine testing as up to 11% of codeine is metabolized to hydrocodone (7), which
could be misinterpreted as unhealthy hydrocodone use.
Methadone Pharmacokinetics
Methadone, as used in the United States, is a racemic compound; the L(R)-
enantiomer is the active component, while the other D(S)-enantiomer is inactive.
Both enantiomers are weak NMDA receptor antagonists; racemic methadone
retards and attenuates the development of opioid tolerance (95). Methadone
meets two important criteria for a medication used in the treatment of an opioid
use disorder: high systemic bioavailability (>90%) with oral administration and
long apparent half-life with long-term administration in humans (96). The
medical safety of long-term methadone maintenance treatment has been well
studied (97).
Oral methadone has a rapid absorption but delayed onset of action, with peak
plasma levels achieved by 2-4 hours and sustained over a 24-hour dosing period
(61,96,98,99). Moreover, the mean plasma apparent terminal half-life of racemic
D,L-methadone in human subjects is around 24 hours (96). The l-enantiomer has
a half-life of 36 hours (95,100,101). Biotransformation of methadone is
accelerated in the third trimester; therefore, methadone dose may need to be
increased in the final stages of pregnancy (102).
When taken on a chronic basis, methadone is stored and accumulated mostly
in the liver (98,103). Methadone plasma levels are relatively constant because of
slow release of unmetabolized methadone into the blood, which extends the
apparent terminal half-life. Methadone is more than 90% plasma protein bound
both to albumin and globulins (102,104). These properties help explain why
methadone maintenance treatment is effective as a once-daily, orally
administered pharmacotherapy for opioid use disorder (28). Methadone is
biotransformed in the liver by the cytochrome P450–related enzymes (primarily
by the CYP3A4 and, to a lesser extent, the CYP2B6, CYP2D6, and CYP1A2
systems) to two N-demethylated biologically inactive metabolites, which
undergo additional oxidative metabolism (29,95). Methadone and its metabolites
are excreted in nearly equal amounts in urine and in feces (105–109). In patients
with renal disease, methadone can be cleared almost entirely by the GI tract,
reducing potential toxicity by preventing accumulation (107–109). Methadone
disposition is relatively normal in patients with mild to moderate liver
impairment (105,110,111). Patients with severe long-standing liver disease have
decreased methadone metabolism and thus slower metabolic clearance of
methadone, yet lower than expected plasma methadone levels as a result of
lower hepatic reservoirs of methadone because of reduced liver size.
Interestingly, due to genetic differences, select patients may require higher doses
of methadone due to “rapid metabolism” of the medication.
Levo-alpha-acetylmethadol (LAAM)
Pharmacokinetics
LAAM, a congener of methadone, shares with methadone the properties of long
duration of effect (48 vs. 24 hours for methadone, in part owing to its active
metabolites norLAAM and dinorLAAM, as well as its steady-state perfusion of
MOP-rs), oral effectiveness (32), and function as a pure opioid agonist, active
mostly at the MOP-r. NorLAAM and dinorLAAM accumulate with chronic
administration. In addition, LAAM and its metabolites bind to tissue proteins
(32).
The clearance of norLAAM and LAAM is similar, whereas the clearance of
dinorLAAM is more prolonged than that of its parent compound (32). The peak
pharmacological effect of LAAM as measured by amount of pupillary
constriction occurred at 8 hours and then diminished at a rate similar to that of
norLAAM metabolism (32).
Because of the metabolism of LAAM by the cytochrome P450 3A4 system–
related microsomal enzymes to norLAAM and dinorLAAM, drug interactions
can occur (eg, rifampin and long-term unhealthy alcohol use tend to induce this
enzyme system). In their presence, increased biotransformation of LAAM could
accelerate the production of norLAAM and dinorLAAM. LAAM metabolism
theoretically could be retarded if hepatic drug metabolism is diminished, as
occurs in the presence of very large quantities of either ethanol, perhaps with
large doses of benzodiazepines, or with intake of cimetidine (32).
Buprenorphine Pharmacokinetics
Buprenorphine undergoes extensive first pass in the liver; thus, it is administered
sublingually with 50%-60% bioavailability. Buprenorphine is metabolized to
norbuprenorphine, due to dealkylation in the cytochrome P450–related enzyme
3A4 system, of which buprenorphine itself is a weak inhibitor (112). Despite the
ceiling effect of buprenorphine as previously described, there have been a
number of reported cases of deaths in Europe with concurrent unhealthy
benzodiazepine use (113). There have been many reports of the intravenous use
of the sublingual preparation of buprenorphine in many countries, which is the
main reason that naloxone is added for deterrence against unhealthy use. A
second formulation of sublingual buprenorphine (combined with naloxone) was
developed in 1984 and is now increasingly used in the United States and
worldwide (97). In this formulation, naloxone will not precipitate withdrawal
when taken sublingually because of its limited oral bioavailability; however, it
may block the initial euphoric effects of buprenorphine if used by the
intravenous route and can also precipitate acute opioid withdrawal (114,115).
Because of the partial agonist ceiling effect, with acute buprenorphine
intoxication, there may be mild mental status changes, mild to minimal
respiratory effects, small but not pinpoint pupils, and essentially stable vital
signs. In some situations, naloxone apparently can improve the respiratory
depression but with limited effect on the other symptoms (115). Patients should
be observed for 24-48 hours.
Initially developed as an analgesic, buprenorphine has been shown in most
studies to be as effective as morphine in many situations. In addition to its
activity in the MOP-r system, buprenorphine has some modest kappa opioid
receptor (KOP-r) antagonist activity as well (116). Owing to its ceiling effect,
increasing buprenorphine doses in humans beyond 32 mg sublingually using the
film version has no greater MOP-r agonist effect and at 16 mg appears to occupy
all the available mu opiate receptors (61,117–119). Buprenorphine has a long
duration of action (24-48 hours) when administered on a chronic basis, not
because of its pharmacokinetic profile, but because of its very slow dissociation
from MOP-r. Two important properties of buprenorphine are (a) its apparent
lower severity of withdrawal signs and symptoms on cessation, compared with
heroin and other opioids, and (b) its reduced potential to produce lethal overdose
when used alone in opioid-naïve or nontolerant persons, because of its partial
agonist properties. Given intravenously, buprenorphine has an apparent beta-
terminal plasma half-life of about 3-5 hours. When given orally, it is relatively
ineffective because of its first-pass metabolism (32), that is, rapid
biotransformation, probably by the intestinal mucosa and, especially, by the
liver. Sublingual preparations of buprenorphine can be film or tablet, both of
which require about 120 minutes for time to peak. However, peak plasma
concentrations of the sublingual tablet and film and mean area under the plasma
concentration time curve are lower than that of the liquid at equivalent doses
(117,120–122).
PHARMACODYNAMICS
The pharmacodynamics of the clinically important MOP-r agonists are wide
ranging, with the most pronounced effects produced in the CNS and GI tract.
The mechanism of action for all of the clinically relevant opioids described
here is at the MOP-r, in which they act preferentially as agonists, except for
pentazocine and buprenorphine, which are partial mu opioid agonists (119) and
low efficacy ligands (antagonists) at kappa receptors (116). The euphorigenic
effects of any opioid agonists are mediated in part by the ventral tegmentum,
where opioid agonist–mediated inhibition of GABAergic neurons results in
disinhibition and thus activation of dopamine neurons extending to the nucleus
accumbens. Norepinephrine-secreting cells in the locus ceruleus appear to play
an important role in opioid withdrawal, whereas both serotonin and dopamine
exert effects on addiction and craving (123,124).
Opioids in general affect heat regulation mechanisms in the hypothalamus.
Body temperature decreases slightly, except with chronic high doses where
temperature may be increased (4). Opioids also act in the hypothalamus to
inhibit the release of gonadotropin-releasing hormone (GNRH) and
corticotropin-releasing hormone (CRH), producing a reduction in luteinizing
hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropin
hormone (ACTH), and beta-endorphin (125). With decrease in these hormones,
plasma concentrations of testosterone and cortisol are lowered. Mu agonists
increase the amount of prolactin in plasma by decreasing dopaminergic
inhibition. Given chronically, there is tolerance to the effects of morphine on the
neuroendocrine system. Mu opioid agonists also tend to have antidiuretic effects
(123,124,126,127) and can cause constriction of the pupil (4). Additionally,
opioids can cause seizures at doses much higher than those used clinically, and
these overdoses can be managed with opioid antagonist medications, such as
naloxone. Of note, naloxone is less potent in antagonizing seizures due to
meperidine in comparison to other opioids such as morphine or methadone,
likely due to its proconvulsant metabolite, normeperidine. Because of the
increased risk of seizure with long-term use of meperidine, it is no longer used
for chronic pain; when used for treatment of acute pain, meperidine should not
be used for >48 hours or at doses >600 mg/d (21).
All opioids must be used cautiously in patients with impaired respiratory
function. Also, opioids have the potential to elevate intracranial pressure (128)
(eg, in the setting of head injury, they can produce an exaggerated respiratory
depression, as well as mental status changes that can confuse the clinical
picture). Typical side effects of all opioids include drowsiness, nausea, and
constipation, while vomiting, pruritus, and dizziness are less common; however,
all of these tend to lessen in intensity over time.
Codeine is commonly used to suppress cough at doses lower than those used
for analgesia (starting with 10-20 mg given orally) and can increase to higher
doses for chronic (lower airway) cough. Codeine reduces cough via a central
mechanism by stimulation of mu receptors on different neuron than those
involved in analgesia or addiction, with doses >65 mg not indicated, owing to
little increased therapeutic effect with increasing side effects (4).
Pentazocine as a mixed agonist–antagonist drug has a “ceiling effect,” like
buprenorphine, which limits the degree of analgesia. Pentazocine can lead to the
development of psychotomimetic side effects, not reversible with naloxone,
suggesting these may not be mediated through MOP-r. Pentazocine also has
affinity for kappa opioid receptors (129). Finally, pentazocine can precipitate
withdrawal in opioid-tolerant patients currently taking opioids, due to its weak
antagonist effects.
Methadone, like all mu opioid agonists, affects multiple organ systems, with
tolerance developing at different rates to each effect. In the treatment of either
opioid use disorder or chronic pain, proper dosing (titrated to the tolerance of the
individual patient) is essential to avoid CNS depression. The precise neuronal
and molecular mechanisms of physical tolerance have not been fully elucidated
(123). However, it has been shown in studies of the d(R)-enantiomer of
methadone (which is relatively inactive at the MOP-r) that this isomer has
modest NMDA antagonist activity, which attenuates the development of
morphine tolerance in rodents, but does not affect physical dependence (30).
Chronic administration of opioids can lead to the gradual development of
tolerance to the effects on hypothalamic-releasing factors, with return to normal
levels and activity of anterior pituitary-derived ACTH and beta-endorphin and
normal ACTH stimulation in ~3 months and resumption of normal menses and
return of plasma levels of testosterone to normal within 1 year (97,125). In
humans, prolactin release is under tonic inhibition by tuberoinfundibular
dopaminergic tone. With the use of short-acting opioids, there is a prompt
increase in the release of prolactin resulting from abrupt lowering of dopamine
levels in the tuberoinfundibular dopaminergic system (130). With heroin use,
thyroid levels may be elevated because of raised thyroid-binding globulin; thus,
there are increased measures without abnormal function (97,125). The
hypothalamic and pituitary effects of opioids can produce antidiuretic effects by
the release of vasopressin (4,125).
Short-acting opioids can cause many effects in the cardiovascular system,
including peripheral vasodilatation, decreased peripheral resistance, reduced
baroreceptor reflexes, histamine release, and decreased reflex vasoconstriction
caused by raised PCO2 (4). In the stomach, hydrochloric acid secretion may be
inhibited, and somatostatin release from the pancreas may be elevated (4).
Acetylcholine release from the GI tract is inhibited, resulting in slowed motility
and reductions in the absorption of many drugs. The presence of increased
appetite has also been noted. Biliary, pancreatic, and intestinal secretions may be
reduced and digestion in the small intestine slowed. In the large intestine, there is
reduced propulsion and higher tone (4,97,125,126). Tolerance to each of these
effects develops with chronic administration.
Other drugs can interact with opioids because of their effects on hepatic enzymes
in the cytochrome P450–related enzyme system (74) (see chart). The drug–drug
interactions with opioids are complex and must be considered on a case-by-case
basis in individual patients. The major categories of drugs potentially interacting
with opioids include both inducers and inhibitors of CYP3A4, as well as
inhibitors of CYP2D6, such as paroxetine (111). CYP3A4 inducers typically
have minimal clinical effects but include rifampin (131), rifabutin (132),
carbamazepine (133), phenytoin (134), and phenobarbital (92); all the same,
given the ability of these medications to increase the rate of metabolism of
opioids, there is a chance that use of these medications in combination with
opioids may induce withdrawal symptoms (135). CYP3A4 inhibitors, which
include fluconazole (136), fluvoxamine (137), fluoxetine (138), paroxetine
(111), and possibly erythromycin and ketoconazole, have shown few clinically
significant drug interactions (29,95,104). A number of studies have examined
specific antiretroviral medications used in the treatment of HIV-1 and their
interaction with methadone. The reported pharmacokinetic interactions, usually
through the CYP3A4 system, affect either methadone or the antiretroviral
medication, which sometimes have clinical manifestations (139,140). Among the
opioids, methadone levels are significantly affected by the regular consumption
of more than four alcoholic drinks per day (141), which can increase levels of
methadone (142).
TOLERANCE DEVELOPMENT
Tolerance may be defined as a loss of any effect after repeated use, leading to the
need for higher doses to get the desired equivalent effect (123,143). All opioid
medications lead to tolerance and physical dependence, but rates of development
vary by medication, different effects, and individuals. Development of tolerance
to opioids does not involve drug disposition and metabolism, but is an interplay
at the single-cell and neuronal system levels (123). Methadone also has modest
NMDA antagonism that may attenuate tolerance (30,79,123). Importantly, the GI
and neuroendocrine side effects of short-acting opioids tend to persist (96).
TOXICITY STATES AND THEIR

MEDICAL MANAGEMENT
Acute opioid overdose is characterized by the triad of altered mental status (ie,
stupor, coma), respiratory depression, and “pinpoint” pupils. On physical
examination, evidence of opioid use, such as marks signaling past or recent
injection in the antecubital fossae, may be noted. Individualized dosing and
reliance on regular clinical assessments are important, as diminished respiration
occurs with opioids until tolerance develops. When any opioid is used beyond
the degree of tolerance that is developed, reduced response to carbon dioxide
centers in the pons and medulla can lead to CO2 retention. Initially, there is
depressed cough (which is mediated by the medulla) as well as nausea and
vomiting, which may be mediated by the area postrema of the medulla and
which disappear rapidly with the development of tolerance. Constriction of the
pupil is the result of parasympathetic nerve excitation. In opioid overdose,
convulsions have been reported, probably because of inhibition of the release of
GABA in the CNS (4). Mydriasis or normal pupils may be observed in patients
with an overdose of meperidine, propoxyphene, dextromethorphan, pentazocine,
and diphenoxylate with atropine (ie, Lomotil) (4,144,145). A full opioid
overdose can be effectively treated with an opioid antagonist. However, repeated
naloxone administration is usually needed, or the overdose may be only
transiently reversed, and the patient may lapse back into coma (141).
MEDICAL COMPLICATIONS OF
OPIOIDS
The two main effects of opioid overdose on the CNS are depression of the
mental status and depression of respiratory activity. A suppressed gag reflex
predisposes the patient to aspiration of gastric contents into the lungs. A few
opioids may cause generalized seizures (eg, high-dose meperidine). Respiratory
depression is the most frequent cause of death (4).
Overdose of opioids may cause noncardiogenic pulmonary edema (NCPE)
and bronchospasm and occurs in 48%-80% of heroin overdoses (4). Overdose
may also cause a release of histamine leading to vasodilatation and orthostatic
hypotension; of note, this effect can be used therapeutically in the treatment of
pulmonary edema and myocardial infarction. Nausea and vomiting from opioids
may stimulate vasovagal tone and cause bradycardia. Prolongation of QTc
interval and torsades de pointes can occur (146), and since a QTc interval >500
ms is considered to be a potential risk factor for sudden death, a recent study of
methadone patients showing a mean QTc value of 428 ms clearly illustrates this
risk with methadone (147,148). Opioid-induced spasm of the sphincter of Oddi
can produce biliary colic.
Intravenous opioid use can lead to bacterial endocarditis; venous thrombosis;
septic pulmonary emboli; emboli of cornstarch and talc (additives) to the retina,
lungs, kidney, and liver; pseudoaneurysms; and mycotic aneurysms (145).
Heroin, morphine, and pentazocine may cause rhabdomyolysis and nephropathy
when used intravenously, leading to glomerulonephritis (145). Centrally
mediated muscle rigidity of the chest and abdominal wall can occur, and
intravenously used opioids may also cause osteomyelitis, septic arthritis,
polymyositis, and fibrous myopathy (4). Injection routes (intravenous,
subcutaneous) of opioids can transmit HIV-1 infection, hepatitis B, hepatitis C,
and bacteria causing cellulitis, skin and neck abscesses, endocarditis, and
botulism (145).
CONCLUSIONS AND FUTURE

RESEARCH DIRECTIONS
The neuronal and molecular basis of opioid tolerance and physical dependence
appears to differ between different end points (eg, analgesia vs. respiratory
depression vs. mediation of reward) and offers much for future research. Two
specific areas for investigation are the genetics of MOP-r function and relating
stress responsivity to opioid function. Understanding the genetics of MOP-r
function is still quite early with a focus on only five single nucleotide
polymorphisms (SNPs) in the coding region of the human OPRM1 gene (149).
Three of these 5 SNPs lead to amino acid changes, and one (the A118G and the
C17T variants) has a high allelic frequency of more than 40% in some ethnic
groups. The C17T variant may have some association with opioid use disorder
(149) and contribute to intersubject variability in response to opioid ligands or
especially the opioid antagonists (149–151). Patients with opioid use disorder
show atypical responses to stress and stressors, as demonstrated by changes in
HPA axis function. During cycles of physical dependence, abstinence, and
relapse, there is a flattened circadian rhythm of glucocorticoid levels, with
increased levels during opioid withdrawal. Additionally, the effects of MOP-r
partial agonists such as buprenorphine on specific indices of neuroendocrine
function have not been extensively studied. Overall, the molecular mechanisms
for partial opioid agonism, with low doses producing agonist and high doses
producing antagonist responses, need a comprehensive theory as well as data to
support that theory, as new opioids are developed. These contributions may also
significantly improve our therapeutic options for analgesia and treatment of
addiction.
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CHAPTER 12
The Pharmacology of Stimulants
David A. Gorelick and Michael H. Baumann
CHAPTER OUTLINE
Definition
Substances Included
Formulations and Methods of Use
Historical Features
Epidemiology
Pharmacokinetics
Pharmacodynamic Actions
Neurobiology
Future Research Directions
DEFINITION
Stimulants are a class of drugs that enhance activity in the central and
sympathetic peripheral nervous systems, chiefly by augmenting
neurotransmission at norepinephrine and dopamine (ie, catecholaminergic)
synapses. Most stimulants exert their effects by binding to presynaptic plasma
membrane monoamine transporters that are responsible for moving previously
released neurotransmitter molecules from the synaptic space back into the
presynaptic neuronal cytoplasm, a process known as uptake. By disrupting the
function of norepinephrine and dopamine transporters, stimulant drugs inhibit
the uptake process and increase extracellular concentrations of norepinephrine
and dopamine, thereby amplifying associated receptor signaling and neuron-to-
neuron transmission.
SUBSTANCES INCLUDED
Stimulants include both naturally occurring plant alkaloids, such as cocaine (Fig.
12-1), ephedra, and khat, and more than a dozen synthetic compounds, such as
the amphetamines and methylphenidate. Most of these are variants of the basic
phenethylamine chemical structure, which is shared by the endogenous
catecholamine neurotransmitters norepinephrine and dopamine (Fig. 12-2). The
wakefulness-promoting agents modafinil and its (R)-isomer, armodafinil, have a
mechanism of action similar to that of stimulants, but a different chemical
structure and reduced propensity for addiction (1). They are not considered in
this chapter.
Figure 12-1 Chemical structures of cocaine, mazindol, and

methylphenidate.
Figure 12-2 Chemical structures of endogenous
catecholamine neurotransmitters (dopamine, norepinephrine)
and phenethylamine stimulant drugs.
All stimulants share the same range of psychological and physiologic effects,
while differing in potency and pharmacokinetic characteristics. Caffeine, the
most widely used stimulant, is considered separately in Chapter 13. 3,4-
Methylenedioxymethamphetamine (MDMA, “Ecstasy”), a structural analogue of
methamphetamine with both stimulant and hallucinogenic characteristics, is
considered separately in Chapter 16.
FORMULATIONS AND METHODS OF

USE
Plant-Derived Stimulants
Several stimulant-containing plants are available for traditional oral use in many
areas of the world. These include coca (containing cocaine) in South America,
ephedra (containing ephedrine) in North America and East Asia, and khat
(containing cathinone) in East Africa and Arabia. Oral use often is culturally
sanctioned and may not be associated with addiction. Use of more potent
formulations (eg, the extracted active chemical) or more rapidly acting routes of
administration has significant addiction potential and is illegal even where oral
formulations are allowed.
Cocaine
Cocaine is an alkaloid with a tropane ester chemical structure (see Fig. 12-1)
similar to that of scopolamine and other plant alkaloids. It occurs in leaves of
several Erythroxylum species (coca bush), especially Erythroxylum coca and
Erythroxylum novogranatense, which grow at altitudes of 1500-6000 feet in the
Andean region of South America (2,3). The leaf contains cocaine (0.2%-1%) and
more than a dozen other tropane alkaloids (such as benzoylecgonine,
methylecgonine, ecgonine, and cinnamoylcocaine), most of which are of
unknown pharmacologic activity. About two dozen other Erythroxylum species
contain little or no cocaine (4). Cocaine exists as two stereoisomers: naturally
occurring (−)-cocaine and (+)-cocaine, which has less affinity for the dopamine
transporter and is relatively inactive in vivo because of its very rapid metabolism
by butyrylcholinesterase (5).
The coca bush is cultivated primarily in Bolivia, Colombia, and Peru.
Domestic use of oral cocaine is legal in these countries, usually as coca tea or by
chewing the leaves (6,7). Coca leaves typically are chewed in conjunction with
lime or plant ash, which alkalinizes the saliva and thus enhances absorption of
the cocaine. Cocaine is legally available (schedule II of the Controlled
Substances Act [CSA]) in the United States only as a 4% or 10% injectable
solution (or powder for reconstitution) or viscous liquid for use as a local or
topical anesthetic. Legal cocaine preparations rarely are diverted for misuse.
Illicit cocaine is smuggled into the United States specifically for recreational
(ie, nonmedical) purposes from its countries of origin. The average purity of
seized cocaine in the United States is about 50% (8). Preparation of illicit
cocaine begins with crushing the coca leaves and heating them in an organic
solvent (often kerosene) to extract and partially purify the cocaine (9). After
several more extraction and filtering steps, the coca paste (now 80%-90% pure)
is heated in an organic solvent (often ether or acetone) with concentrated acid to
convert it to salt form. The salt is readily converted back to the base by heating it
in an organic solvent at basic pH. This process is known as “freebasing” and was
practiced by cocaine users during the 1980s, before cocaine base (or “freebase”)
was widely available on the retail street market. “Crack” as a street name for
base cocaine reportedly derives from the crackling sound made during this
heating process.
Cocaine is available for street use in two forms: base and salt (10,11). These
forms have different physical properties, which favor different routes of
administration. The base has a relatively low melting point (98°C) and vaporizes
before substantial pyrolytic destruction has occurred. This allows cocaine base to
be smoked, though the majority of the cocaine may be in the form of small
particles (<5 μm) that reach the alveoli, rather than true cocaine vapor (12).
Cocaine base is relatively insoluble in water (alcohol to water solubility ratio of
100:1), making it difficult to dissolve for injection purposes. In contrast, cocaine
salt does not melt at less than 195°C, so heating it for smoking results in
destruction of most of the cocaine. However, cocaine salt is highly water soluble
(alcohol to water solubility ratio of 1:8), making it easy to dissolve for injection
purposes and facilitating absorption across mucus membranes. Regardless of the
chemical form or route of administration, the cocaine molecule exerts the same
actions once it reaches the brain or other target organ (10).
Adulterants are added (ie, the cocaine is “cut”) to enhance dealer profits.
These include both inert fillers that look like cocaine (such as dextrose, lactose,
mannitol, or starch) and active chemicals that either mimic the local anesthetic
effect of cocaine (such as benzocaine, lidocaine, or procaine) or provide some
psychoactive effect (such as ephedrine, amphetamine, caffeine, or phencyclidine
[PCP]) (13). The veterinary antihelminthic agent levamisole is increasingly
common as a cocaine adulterant, found in more than 60% of analyzed street
cocaine samples in the United States (14). Cocaine adulterated with levamisole
is associated with serious side effects, including agranulocytosis and cutaneous
vasculitis. Street cocaine may also contain contaminants from the preparation
process (such as benzene, acetone, or sodium bicarbonate).
Ephedra
Ephedrine and pseudoephedrine are naturally occurring alkaloids with a
phenethylamine chemical structure (see Fig. 12-2) that are found in several
Ephedra species (especially Ephedra sinica, Ephedra equisetina, and Ephedra
gerardiana) (15,16). Ephedra is a preparation of dried young branches of
Ephedra species, typically containing 1%-3% ephedrine. This may be converted
into a capsule, tincture, liquid extract, or tea. Ephedra products are widely used
in East Asia and North America; they appear in the pharmacopoeias of China,
Japan, and Germany.
Ephedra products often are advertised as legal versions of or alternatives to
the more strictly regulated manufactured stimulants. They may appeal to
consumers as safer than synthetic stimulants because they are “natural” or
“herbal.” Synthetic ephedrine and pseudoephedrine also are available as tablets
or capsules (see below). Ephedra alkaloids have the same range of psychological
and physiological effects as do cocaine and amphetamines. There is limited
evidence of their efficacy for weight loss in obese individuals (4,17). Ephedra
use has been associated with severe cardiovascular and central nervous system
(CNS) effects, including death, leading to its banning from the US market in
2006 (18).
Khat
Khat is the common term for preparations of the Catha edulis plant, which is
native to East Africa (Sudan to Madagascar) and the southern Arabian peninsula
(Yemen) (19,20). Fresh khat leaves contain at least two stimulant alkaloids with
phenethylamine chemical structures: cathinone (present at 1%-3%) and cathine
(norpseudoephedrine).
Cathinone is a Schedule I controlled substance; cathine is in Schedule IV.
Cathinone displays neuropharmacological potency similar to amphetamines (21).
Recreational use of potent synthetic cathinone congeners such as mephedrone,
methylone, and 3,4-methylenedioxypyrovalerone (MDPV), often marketed as
“bath salts,” has increased markedly around the world in the past decade (see
“Synthetic Stimulants” below).
Khat use has been a widely accepted social custom for centuries, apparently
predating the use of coffee (caffeine). The leaves are used in the same way as
coca leaves in South America, that is, chewed and kept in the cheek for several
hours. Less often, the leaves are brewed into tea or crushed with honey to make
a paste. Moderate use reduces fatigue and appetite. Compulsive use may result in
manic behavior or psychotic symptoms such as paranoia or hallucinations. Up to
one-third of regular users may develop a substance use disorder (SUD) (22).
Khat loses much of its potency within 2 days of harvesting, as cathinone is
converted to the much less potent cathine. Some khat use is found among
immigrant communities in Europe, but there appears to be minimal use of khat
in the United States.
Synthetic Stimulants
More than a dozen synthetic stimulant medications are legally available in the
United States, either by prescription (Table 12-1) or over the counter (Table 12-
2). Most represent variations on the basic phenethylamine structure (see Fig. 12-
2). Common trade and street names, controlled substance scheduling, clinical
uses (FDA-approved and otherwise), and typical doses are listed in Tables 12-1
and 12-2. All legal stimulants, other than cocaine, are sold for oral use in tablet,
capsule, or liquid form.
TABLE 12-1 Stimulants Available by Prescription in the

United States
aNot labeled for this indication by the U.S. Food and Drug Administration.
ADHD, attention deficit/hyperactivity disorder; CSA, U.S. Controlled Substances Act.
TABLE 12-2 Stimulants Available as Over-the-Counter

Preparations in the United States
Several stimulants are available in extended or sustained-release formulations

(23–25), chiefly prescribed for treatment of attention deficit/hyperactivity
disorder (ADHD). Methylphenidate is also available as a transdermal patch,
which releases drug at a rate of 1.1-3.3 mg/h, depending on patch size (26).
Amphetamine is available as a prodrug, lisdexamfetamine, consisting of D-
amphetamine coupled to the amino acid L-lysine (27). The active drug is formed
as the inactive lysine is hydrolyzed by enzymes in the intestines and liver. All
these formulations have two theoretical advantages over conventional immediate
release formulations: improved patient compliance and effectiveness because of
longer duration of action and reduced addiction liability because of slower onset
of action and weaker peak subjective effects (28).
Some over-the-counter (OTC) stimulants also are available in aerosolized
formulations for nasal inhalation (insufflation) for use as decongestants.
Phenylephrine is available as a sterile solution for parenteral administration to
treat hypotension.
Prescription synthetic stimulants are often misused (ie, used for nonmedical
purposes, rather than as prescribed), especially by adolescents and young adults
(29). Amphetamines, especially highly pure crystallized methamphetamine
(“ice”), may be used intranasally or smoked, as is cocaine. The stimulants may
be obtained via a physician’s prescription, diverted from a relative or friend who
has a prescription, or purchased illegally (30). If oral administration is not
intended, the original tablet or capsule may be crushed or opened to allow the
drug to be taken intranasally or mixed with water for injection. Amphetamines,
especially methamphetamine, are often synthesized in clandestine laboratories
directly for illicit use. This can be done with standard chemical reactions applied
to legally available precursors. For example, methamphetamine
(desoxyephedrine) can be made by reducing ephedrine or pseudoephedrine. For
this reason, retail purchases in the United States of products containing
ephedrine or pseudoephedrine are limited to 3.6 g/d and 9 g/mo and require
photographic identification.
Stimulants with a phenylisopropylamine structure (such as amphetamine,
methamphetamine, ephedrine, pseudoephedrine, and phenylpropanolamine) have
a chiral (stereoisomeric) center at the alpha-carbon atom (see Fig. 12-2), and so
exist in two (or more) stereoisomer forms that differ in pharmacodynamic and
pharmacokinetic properties (31,32). The D- or S-(+) isomer generally has three to
five times the CNS activity and about one-third the half-life of the L- or R-(−)
isomer. The L-isomers have more peripheral alpha-adrenergic activity. For
example, D-methamphetamine is a potent CNS stimulant, whereas L-
methamphetamine (L-desoxyephedrine) has been used as a decongestant (as in
the Vicks nasal inhaler) (33). Methylphenidate exists in four stereoisomeric
forms, of which the D-threo enantiomer is the active one (34).
The recreational use of synthetic stimulants unrelated to prescription
medications has increased substantially in recent years. These compounds are
typically synthetic analogues of cathinone and are now classified in Schedule I.
Products containing synthetic cathinones are purchased over the Internet or at
retail outlets not typically associated with illicit drugs and marketed with
innocuous names (eg, “bath salts,” “plant food”) as “legal” alternatives to
cocaine and methamphetamine (35). Synthetic cathinones fall into two broad
categories: pyrrolidine-containing compounds like MDPV and ring-substituted
cathinones like 3,4-methylenedioxymethcathinone (methylone). MDPV is a
common constituent of bath salts products, whereas methylone is often found in
counterfeit MDMA (Ecstasy) tablets. Synthetic cathinones exert potent
amphetamine-type stimulant effects and can cause serious cardiovascular and
neurological side effects requiring emergency medical care (36).
Clinical Uses
Cocaine is used clinically as a local or topical anesthetic with vasoconstrictor
properties, chiefly for eye, ear, nose, or throat surgery or procedures (37). Other
prescription stimulants generally are used for one of several FDA-approved
indications: ADHD in both children and adults (23,25), narcolepsy and excessive
daytime sleepiness (38,39), and appetite suppression to promote weight loss in
exogenous obesity (40) (see Table 12-1). Stimulants prescribed for ADHD are
misused by about 10% of patients for whom they are prescribed (41).
OTC stimulants generally are used for decongestion (42) and
bronchodilation in the treatment of asthma, upper respiratory infections, allergic
rhinitis, sinusitis, or bronchitis and for appetite suppression to promote weight
loss in exogenous obesity (both of which are FDA-approved indications) (see
Table 12-2). Parenteral phenylephrine also is approved by the FDA as an adjunct
to prolong the duration of spinal anesthesia, to terminate paroxysmal
supraventricular tachycardia (probably indirectly by stimulation of arterial
baroreceptors), and for immediate, short-term treatment of hypotension
(especially when due to anesthesia, drugs, or hypersensitivity reactions).
In addition to their FDA-approved indications, oral stimulants have a long
history of accepted clinical use for other indications (43). Amphetamines and
methylphenidate are used as tertiary or adjunctive (augmentation) treatment for
major (unipolar) or bipolar depression (44,45) and as quick acting (2- to 3-day),
short-term antidepressants in persons who are elderly, medically ill, and HIV
infected or those with neurological conditions such as stroke or traumatic brain
injury, especially those who cannot tolerate the side effects of standard
antidepressants (46). Such patients may exhibit apathy, fatigue, and psychomotor
retardation, rather than a full-blown classic depressive syndrome. Often, it is
unclear whether the beneficial effect of stimulants in such patients is due to the
drugs’ activating effects or to true antidepressant actions. Stimulants have been
used to improve functional recovery after stroke and traumatic brain injury
(47,48) and to reduce fatigue in palliative care (49), but their efficacy appears
limited. Amphetamines, methylphenidate, and mazindol have been used to
potentiate opiate analgesia and to counteract opiate-induced sedation and
respiratory suppression, thus allowing larger doses of opioids to be used.
Cocaine has been used for this purpose as part of Brompton’s cocktail (with
alcohol and an opioid) in the treatment of cancer pain. Ephedrine and
phenylephrine still are used parenterally to counteract hypotension associated
with spinal anesthesia (especially in obstetrical and urological surgery). Most
other clinical uses of stimulants for their pressor effect have been superseded by
more selective agents.
There is no evidence that medical use of stimulants at therapeutic doses in
appropriately diagnosed patients leads to a stimulant use disorder or increases
the risk of serious adverse events, although there are little data from long-term,
controlled trials (50). Prospective, longitudinal studies of children receiving
stimulant treatment for ADHD find no increased risk of developing a SUD (51).
Nonmedical Use and Addiction

Oral stimulants (both prescription and OTC) are widely used in work, school,
military, and sports settings, often without medical supervision, for their alerting,
antifatigue, sleep-suppressing, and performance-enhancing properties (52,53).
The antifatigue and sleep-suppression effects of stimulants have been well
demonstrated in laboratory and field studies. Enhancement of cognitive and
psychomotor performance is more difficult to demonstrate in controlled studies
and occurs more robustly in persons who already are fatigued or sleep deprived.
Stimulants are used by athletes to improve performance, especially in endurance
sports such as cycling, which require anaerobic exercise, although there is little
published evidence of their efficacy (54–56). Stimulants of all types (illicit,
prescription, and OTC) are banned by the World Anti-Doping Agency and many
other sports organizations (57).
All stimulants have a potential for misuse and addiction, varying only in
their potency. Cocaine, amphetamine, and methamphetamine have high
addiction potential, as reflected in their placement in Schedule II of the CSA.
Community-based interview surveys suggest that up to one in six persons who
use cocaine and one in nine who use prescription stimulants for other than
medical purposes will develop a moderate–severe stimulant use disorder (58).
Even higher rates are found in treatment-seeking populations: up to four-fifths of
those who have used cocaine several times and up to half of those who have
used amphetamines become addicted (59). Heavier users and those who use the
intravenous and smoked forms are more likely to become addicted than are
lighter users or those who use the intranasal and oral forms (59–61). Even lower
potency stimulants in Schedule IV, such as pemoline and phentermine, or OTC
stimulants, such as ephedrine, pseudoephedrine, and phenylpropanolamine, have
been misused or result in a stimulant use disorder (62).
Studies of pairs of fraternal (dizygotic) and identical (monozygotic) twins
suggest that there is a genetic influence both on initiation and use of stimulants
and on stimulant use disorder (63,64). Findings are best explained by a single
genetic factor influencing illegal drugs (as distinct from legal drugs such as
alcohol, tobacco, and caffeine), which may account for about three-fourths of the
variance in cocaine use disorder and one-fourth of the variance in amphetamine
use disorder. There do not appear to be significant gender differences in genetic
influence. Efforts to identify a specific gene or genes responsible for stimulant
use disorder have not been successful. Many candidates have been identified in
genome-wide association studies, but none has been robustly replicated (65,66).
The greater addiction liability of intravenous and smoked (as opposed to oral
and intranasal) routes of administration is due to their faster rate of drug delivery
to the brain (6-8 seconds, in the case of smoking), resulting in a faster onset of
psychological effects (67,68). This faster onset is associated with a more intense
pleasurable response and greater addiction liability (the so-called “rate
hypothesis” of psychoactive drug action) (28,69).
Stimulants are used in a variety of patterns (70,71). “Binge” use involves
short periods of heavy use (eg, on weekends or after payday), separated by
longer periods of little or no use. Others may use frequently for an extended
period until their finances are exhausted or their access to drug is interrupted. A
small number of users may use low doses daily without dose escalation over
time. Some of these users may be self-medicating an underlying
neuropsychiatric disorder such as ADHD or narcolepsy. Typical cocaine doses
are 12-15 g orally (coca leaf chewing), 20-100 mg intranasally, 10-50 mg
intravenously, and 50-200 mg smoked.
Stimulant use is associated with agitation and aggressive behavior (72). Low
doses increase aggressive behavior in human experimental laboratory models of
aggression (eg, willingness to administer electric shock) (73).
Unintended use of cocaine may occur in persons who swallow the drug in
their possession to avoid arrest or prosecution (“body stuffers”) or who swallow
large quantities to transport it without detection by law enforcement authorities
(“body packers,” “mules”) (74,75). The drug may be wrapped in plastic bags,
balloons, condoms, paper, aluminum foil, or a combination. If the wrapper fails,
the carrier may be exposed suddenly to large doses of cocaine in the
gastrointestinal tract, resulting in severe acute cocaine intoxication.
Stimulants often are used in combination with other drugs, either
concurrently or sequentially. Concurrent use of a stimulant and an opioid,
sometimes in the same injecting syringe, is considered by many users to provide
a qualitatively better subjective effect (“high”) than either drug alone (76,77).
Concurrent intravenous use of cocaine plus heroin is termed speedballing.
Combined use of oral amphetamine plus an oral opioid (such as codeine) also is
common. Human experimental studies suggest that the acute psychological
effects of cocaine are somewhat enhanced with concurrent administration of
cocaine and an opioid (77,78). Other drugs sometimes used concurrently with
smoked cocaine include PCP, marijuana, or tobacco (78,79). CNS depressant
drugs, such as alcohol, benzodiazepines, opioids, and marijuana, often are used
after cocaine use to temper unpleasant effects of cocaine intoxication (such as
anxiety, paranoia, restlessness) and/or to relieve symptoms of cocaine
withdrawal.
HISTORICAL FEATURES
Naturally occurring plant alkaloids have been used for their CNS stimulant
properties for thousands of years (11). Chinese medicine has used the herbal
preparation ma-huang (ephedra) for at least 5000 years. Chewing of coca leaves
has been prevalent in the Andean regions of South America for at least 2000
years (80). Coca leaves and pottery images of figures with bulging cheeks
(presumably wads of coca leaf) have been found in 1400-year-old Peruvian
burial sites. The Spanish conquerors of South America found coca leaf chewing
common in the Andean regions and noted its association with increased energy
and decreased need for food and sleep. They did not discourage the practice,
which continues to this day and is legal in Bolivia and Peru (6,7).
Coca received little attention in Europe until the second half of the 19th
century. In 1860, a German graduate student, Albert Niemann, isolated cocaine
as the active ingredient of coca leaf. This discovery helped generate the
popularity of cocaine-containing products throughout Europe and North
America. Cocaine-containing wines, such as Vin Mariani (containing 6-8 mg of
cocaine per ounce), were widely advertised and endorsed by prominent political
and cultural figures. A nonalcoholic beverage (containing 4.5 mg of cocaine per
6 oz) was introduced in 1886 and quickly became one of the world’s most
popular soft drinks: Coca-Cola. A fluid extract of coca for medical use
(containing 0.5 mg of cocaine per mL) appeared in the US Pharmacopeia in
1882. The first specific use of cocaine in medicine came in 1884, when the
German ophthalmologist Koller discovered its efficacy as a local anesthetic
during surgery. In the same year, Sigmund Freud published his monograph, Uber
Coca, describing the first systematic study of cocaine’s psychological effects
(albeit with a sample of one, himself) and suggesting its use as a treatment for
morphine addiction.
With widespread use of cocaine came increasing reports of adverse effects.
The first report of cocaine-associated cardiac arrest and stroke was published in
1886. By 1903, cocaine had been removed from Coca-Cola. In 1914, the
Harrison Narcotic Act banned cocaine from OTC medications, beverages, and
foods in the United States, restricting its use to prescription drugs. For the next
50 years, cocaine remained largely out of public view and medical attention,
except for limited use as a local anesthetic.
Synthetic stimulants first appeared with the synthesis of amphetamine in
1887 (by Edeleanu) and of methamphetamine in 1919. These attracted little
attention until amphetamine became popular as an OTC bronchodilator (in the
Benzedrine inhaler) in the early 1930s. By 1933, its CNS stimulant properties
were recognized, leading to its use for weight loss, narcolepsy, depression, and
childhood hyperactivity. Amphetamine’s advantages also were recognized by
persons with a stimulant addiction. It largely replaced cocaine in illicit use
because of its low cost, ready availability, and longer duration of action. This
growing abuse pattern led to a switch in 1937 from OTC to prescription-only
status. During World War II, amphetamine was widely used by the Allied and
Axis countries to enhance the performance of troops and factory workers. After
the war, widespread abuse in Japan and Sweden of large leftover stockpiles led
to tight restrictions on amphetamine manufacture and dispensing. In response to
increasing rates of intravenous misuse of amphetamine extracted from
Benzedrine inhalers, the US Food and Drug Administration (FDA) banned the
inhalers in 1959. With passage of the Controlled Substances Act in 1970,
cocaine, amphetamine, and methamphetamine were placed in Schedule II
because they have high potential for misuse and accepted medical use only with
severe restrictions.
EPIDEMIOLOGY
There are substantial geographic and sociodemographic differences in the
epidemiology of stimulant use (81). In 2014, there were an estimated 18.2
million cocaine users worldwide, representing 0.4% of the 15- to 64-year-old
population. About one-quarter (28%) were in North America (5.1 million; 1.6%
prevalence), where prevalence has declined almost one-quarter over the past 15
years. In contrast, use is increasing in West and Central Europe (3.5 million;
1.1%), South America (4.2 million users, 1.5%), Central America and the
Caribbean (0.35 million users, 0.6%), West, Central, and Southern Africa (2.4
million users, 0.7%), and Oceania (0.39 million users, 1.5%). Cocaine use is also
increasing, but remains at low prevalence, in East and Southeast Europe (0.51
million; 0.2%), North and Eastern Africa (0.03 million; 0.02%), and Asia (1.3
million; 0.1%). In 2014, there were an estimated 35.6 million (0.8% prevalence)
global nonmedical users of amphetamines and prescription stimulants. Such
misuse is most prevalent in Oceania (0.5 million; 1.9%), North America (4.6
million; 1.4%), South America (2.6 million, 0.9%), Central America (0.24
million; 0.9%), Africa (5.5 million, 0.9%), the Caribbean (0.2 million, 0.8%),
and Asia (19.7 million, 0.7%). There is relatively less use in West and Central
Europe (1.6 million; 0.5%) and in East and Southeast Europe (0.84 million;
0.4%). These patterns of stimulant use probably reflect availability and access,
because the only source of cocaine is the Andean region of South America,
whereas amphetamines are readily synthesized anywhere.
Oral use of cocaine has a long cultural tradition and is legal in Bolivia and
Peru, where surveys estimate a lifetime prevalence of coca leaf use up to 90%
and 30%, respectively (82). Purified cocaine, suitable for intravenous, smoked,
or intranasal administration, is illegal in all Andean countries. The lifetime
prevalence of such cocaine use is similar to that reported in North America.
A detailed view of stimulant epidemiology in the United States comes from
the National Survey on Drug Use and Health (NSDUH), which annually surveys
a representative sample of household residents 12 years and older that is
sufficiently large (about 67,500 annually) to generate valid population estimates
of drug use. NSDUH data may tend to underestimate overall drug use because
the survey sample does not include some groups in which drug use is likely to be
higher, such as persons in correctional settings, homeless persons, hospital
patients, and residential college students. The NSDUH includes nonmedical use
of prescription drugs but does not measure use of OTC medications or dietary
supplements, such as ephedra or caffeine (see Chapter 3). Information on
adverse consequences of stimulant use comes from the Drug Abuse Warning
Network (DAWN). DAWN is a nationwide survey of 233 general, nonfederal,
short-stay hospitals with 24-hour emergency departments, selected to be
representative of all US hospitals, last conducted in 2011. Data are collected on
patient visits associated with the use of illegal drugs or nonmedical use of
prescription and OTC medications.
According to NSDUH data, cocaine is the second most widely used illegal
drug in the United States, after marijuana (83). The 2015 NSDUH estimated that
38.7 million Americans (14.5% of the US population 12 years old or older) had
used cocaine at some time during their lifetimes (9 million [23% of cocaine
users] by smoking “crack” cocaine); 4.8 million (1.8% of the population) had
used cocaine (0.83 million [17.3%] by smoking) within the preceding year; and
1.9 million (0.7% of the population) had used cocaine (0.35 million [18.4%] by
smoking) within the preceding month, considered current use. There were an
estimated 968,000 new cocaine users in 2015 (37,000 [3.8%] by smoking), with
a mean age of 22 years. An estimated 896,000 Americans met psychiatric
diagnostic criteria for cocaine use disorder in 2015; an estimated 615,000 people
received specialty treatment for their cocaine use.
Cocaine use occurs in all segments of American society but is substantially
more prevalent in certain population groups. Data from the 2001-2003 National
Comorbidity Survey Replication (a representative, community-based sample of
5692 adults) suggest that the most likely cocaine user is an unemployed,
divorced/separated, non-Hispanic white male high school dropout or graduate in
his 20s, living in a nonrural area in the Northeast or West, for whom religion is
not important (84). These associations between cocaine use and age, gender,
education level, and employment and marital status are generally found
throughout the world (85).
Cocaine use is highly associated with legal substance use and with
psychiatric syndromes. Cigarette smokers or heavy alcohol drinkers are each at
least 10 times more likely to use cocaine than are nonsmokers or moderate
(nonbinge) drinkers. Current cocaine users are twice as likely to have symptoms
of depressive or anxiety disorders than are nonusers (86).
The 2015 NSDUH estimated that 14.5 million Americans (5.4% of the US
population aged 12 years or older) had used methamphetamine at some time
during their lifetimes; 1.7 million (0.6%) had used methamphetamine and 5.3
million (2%) had misused prescription stimulants within the preceding year; and
0.90 million (0.3%) were current (past month) methamphetamine users and 1.7
million (0.6%) were current misusers of prescription stimulants (83). There were
an estimated 0.23 million new methamphetamine users and 1.3 million new
prescription stimulant misusers in 2015, with a mean age of 28.1 and 24.4 years,
respectively. An estimated 872,000 (0.3%) Americans met psychiatric diagnostic
criteria for methamphetamine use disorder and 426,000 (0.2%) for prescription
stimulant use disorder. In 2015, an estimated 443,000 people received specialty
treatment for their methamphetamine use and 139,000 people for their
prescription stimulant misuse.
Stimulant use often is associated with adverse consequences. In the 2011
DAWN survey, cocaine was the drug associated most often with visits to hospital
emergency departments, with an estimated half-million visits (40.3% of all illicit
drug-related visits), a rate of 162 cocaine-associated visits per 100,000
population (87). Amphetamines were associated with 160 thousand visits
(12.8%), a rate of 51.3 visits per 100,000 population. There were 15,514
stimulant-related deaths among 15- to 64-year olds in the United States from
1999 through 2009 (based on death certificate data collected by the Centers for
Disease Control and Prevention), a rate of 0.97/100,000 person-years in 2009
(88). The highest death rates were among American Indians or Alaska Natives
and those living in the West.
Only a minority of stimulant users appear to seek SUD treatment. In 2013,
there were 102,000 admissions (9.7% of all admissions) of individuals reporting
cocaine as their primary drug to publicly funded and/or licensed SUD treatment
programs, a 60% decrease over the preceding decade (89). Two-thirds (68%) of
these admissions involved smoked cocaine. Another 139,000 admissions
(13.2%) were for other stimulants, a 3% increase over the preceding decade.
PHARMACOKINETICS
Absorption and Distribution
Route of administration has a major effect on the pharmacokinetic characteristics
of stimulants (90). Smoked stimulants (such as cocaine base or
methamphetamine) are rapidly absorbed through the lungs and probably reach
the brain in 6-8 seconds. Thus, the onset and peak effect occur within minutes of
administration. As the stimulant redistributes from the brain, there is a rapid
decline in effect. Intravenous administration produces peak brain uptake in 4-7
minutes, based on positron emission tomography (PET) studies with
radiolabeled cocaine (91). Greatest cocaine uptake occurs in the striatum
(caudate, putamen, and nucleus accumbens) and least uptake in the orbital cortex
and cerebellum. Clearance to half-peak brain levels requires 17-30 minutes and
is fastest in the orbital cortex, thalamus, and cerebellum and slowest in the
striatum. The rapid offset after rapid onset often is experienced as a “crash” by
users of smoked or intravenous stimulants. Heavy cocaine users have about 20%
less brain cocaine uptake than do healthy nonusers (92). The mechanism of this
difference is not known but could be related to differences in plasma protein
binding or permeability of the blood–brain barrier.
Intranasal and oral stimulants have a slower absorption and onset of effect
(30-45 minutes), a longer peak effect, and a more gradual decline from peak.
The peak intensity of effect is weaker than with smoked or intravenous
administration because less active drug reaches its site of action in the brain.
Coca leaf chewing produces less than half the peak cocaine plasma
concentrations of an equivalent dose of intranasal cocaine (93). However, even a
single oral dose of cocaine (such as 2 mg in a cup of coca tea) may yield
detectable urine concentrations of cocaine metabolites (94). Pharmacokinetic
parameters for oral stimulants are given in Table 12-3.
TABLE 12-3 Pharmacokinetic Parameters of Oral

Stimulants
aUrine pH dependent: lower pH yields shorter half-life.

Tmax, time of maximum plasma concentration (in hours); T1/2, half-life (in hours); Vd, apparent volume
of distribution (in L/kg of body weight); pKa, acid dissociation constant (pH at which drug is 50%
ionized); Fb, fraction of bound drug.
From Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 7th ed. Foster City: Chemical
Toxicology Institute, 2004.
Cocaine is well absorbed through mucus membranes and also is absorbed

through intact skin or by passive inhalation of smoked cocaine or aerosolized
particles (95–97). Passive exposure can result in adverse medical effects in
infants (98,99) and detectable urine concentrations of cocaine metabolites in
medical and laboratory personnel (97,100). In many cases, these concentrations
are too low to trigger a positive result on routine urine drug testing.
Stimulants distribute into most tissues of the body. Cocaine is rapidly taken
up into the heart, kidney, adrenal glands, and liver (5). In addition to blood and
urine (101), cocaine and its hydrolytic metabolites, amphetamines, phentermine,
and ephedrine and its analogues appear in hair (102–104), sweat (105), oral fluid
(saliva) (106–108), nails (109), and breast milk (110), and cross the placenta to
appear in umbilical cord blood, amniotic fluid, and meconium (109). Analysis of
these tissues and fluids is used for drug detection in workplace, legal, and
treatment settings (111). Stimulants can also be detected postmortem in body
fluids and tissues (112).
Metabolism
In humans (and other primates), 95% of cocaine is metabolized by hydrolysis of
ester bonds to benzoylecgonine (the primary urinary metabolite) and ecgonine
methyl ester by the action of carboxylesterases in the liver and
butyrylcholinesterase in the liver, plasma, brain, lung, and other tissues
(93,113–115). The remaining 5% of cocaine is N-demethylated to norcocaine by
the CYP3A4 isozyme of the liver cytochrome P450 microsomal enzyme system.
This is the predominant metabolic pathway in rodents.
Norcocaine has some pharmacological actions similar to those of cocaine
and is hepatotoxic. This may account for the significant hepatotoxicity of
cocaine in rodents, which is not found in primates. Cocaine’s hydrolytic
metabolites appear to be much less active pharmacologically, though this has not
been well studied (116,117).
Amphetamines are metabolized in the liver via three different pathways:
deamination to inactive metabolites, oxidation to norephedrine and other active
metabolites, and parahydroxylation to active metabolites (118). Amphetamine
itself is the initial metabolite of methamphetamine.
When cocaine is smoked, a pyrolysis product is formed (methylecgonidine
or anhydroecgonine methyl ester), the presence of which allows identification of
the smoked route of administration (90,93,115).
Elimination
Stimulants and their metabolites are largely eliminated in the urine (31,93).
Benzoylecgonine is the cocaine metabolite found in highest concentration in
urine for several days after cocaine use. It is this substance, rather than the parent
drug cocaine, that actually is measured in routine urine drug tests for cocaine. GI
absorption and urinary elimination of amphetamines is highly pH dependent.
Because amphetamines are weak bases (pKa around 9.9) (118), acidification of
the GI tract or urine substantially decreases absorption and increases excretion,
respectively (93). Conversely, alkalinization of the GI tract or urine can increase
GI absorption and reduce excretion to negligible levels. This fact is exploited by
people who use drugs and take large doses of sodium bicarbonate to prolong the
action of amphetamines and reduce the amount present in the urine for detection
by drug tests (119).
The primary drug interaction of stimulants that is of clinical concern is with
other stimulants or with other medications that also enhance catecholamine
activity. Such interactions risk overstimulation of the sympathetic nervous
system, with possible cardiac arrhythmia, hypertension, seizure, cardiovascular
collapse, and death. The major potential for interaction is presented by
monoamine oxidase inhibitors (MAOIs), which are used as antidepressants.
MAOIs enhance catecholamine activity by inhibiting a major metabolic pathway
for catecholamines. Potent prescription stimulants, such as amphetamine and
methamphetamine, should not be used within 2 weeks of MAOI use, as the
former’s blockade of catecholamine uptake, combined with the latter’s inhibition
of catecholamine breakdown, could result in dangerously high levels of
catecholamine activity. Stimulants should be used cautiously in conjunction with
tricyclic antidepressants, many of which block presynaptic reuptake of
catecholamines.
Alcohol used in conjunction with cocaine often results in enhanced or
prolonged cocaine effects, in part because of formation of a new
pharmacologically active compound, cocaethylene (120). Cocaethylene has
actions similar to, but less potent than, those of cocaine, with a longer half-life.
However, human laboratory studies of the cocaine/alcohol/cocaethylene
interaction have yielded inconsistent results.
PHARMACODYNAMIC ACTIONS

Intoxication
All stimulants produce a similar range of psychological, behavioral, and
physiological effects, with the intensity and duration depending on potency,
dose, route of administration, and duration of use (see Chapter 54, “Management
of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club Drug
Intoxication and Withdrawal”). The initial effects—usually desired—include
increased energy, alertness, and sociability; elation or euphoria; and decreased
fatigue, decreased need for sleep, and decreased appetite (121). The intense
pleasurable feeling has been described as a “total body orgasm” (122). These
effects may occur after 5-20 mg of oral amphetamine, methamphetamine, or
methylphenidate; 100-200 mg of oral cocaine; 40-100 mg of intranasal cocaine;
or 15-25 mg of IV or smoked cocaine (122,123). Such single oral doses of
stimulants improve cognitive and psychomotor performance in subjects whose
performance has been impaired by fatigue, sleep deprivation, or alcohol,
especially in tasks that require focused and sustained attention (vigilance)
(123,124).
There is less consistent evidence that stimulants are of any benefit in
subjects who are fully alert and attentive or engaged in tasks involving learning,
memory, or problem solving. With increasing potency, dose, duration of use, or a
more efficient route of administration, stimulant effects often progress to include
dysphoric effects such as anxiety, irritability, panic attacks, interpersonal
sensitivity, hypervigilance, suspiciousness, paranoia, grandiosity, impaired
judgment, and psychotic symptoms such as delusions and hallucinations. Among
nontreatment-seeking users, 10%-40% may have sleep disturbance and weight
loss (due to appetite suppression), and up to 25% may experience severe
paranoia and/or hallucinations (125,126). The proportion of stimulant users
experiencing paranoia or psychotic symptoms varies with intensity and duration
of use and degree of addiction and has been as high as 100% in some studies,
even among community-based and non–treatment-seeking samples (127–129).
Patients with stimulant psychosis may closely resemble those with acute
schizophrenia (130,131)—perhaps not surprising, given that both conditions
share the presumed pathophysiology of excessive brain dopamine activity (132).
Cocaine-induced psychosis may differ from acute schizophrenic psychosis in
being marked by less thought disorder and bizarre delusions and fewer negative
symptoms such as alogia and inattention (129). Stimulant-induced hallucinations
may be auditory, visual, or somatosensory (127,133). Tactile hallucinations are
especially typical of stimulant psychosis and include the sensation of something
(eg, insects) crawling under the skin (“formication,” “cocaine bugs”).
Parallel behavioral effects include restlessness, agitation, tremor, dyskinesia,
and repetitive or stereotyped behaviors such as picking at the skin or foraging for
drug (“punding,” “hung-up activity”) (72,134). Associated physiological effects
include tachycardia, pupil dilation, diaphoresis, and nausea, reflecting
stimulation of the sympathetic nervous system. Criteria for the psychiatric
diagnosis of stimulant intoxication are given in Appendix 4. Treatment of acute
stimulant intoxication is reviewed in Chapter 54, “Management of Stimulant,
Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and
Withdrawal.” Cocaine and the more potent synthetic stimulants (such as
amphetamines) produce these adverse effects at readily available doses by any
route of administration. Less potent oral stimulants may require chronic, high-
dose use or diversion to intravenous use to cause these effects. Even OTC
stimulants have been associated with severe psychological effects, misuse, and
addiction.
There is wide individual variability in the response to stimulants. The
reasons are poorly understood but presumably are related to differences in
genetics, psychological characteristics (including personality traits), previous
drug experience, the setting in which the drug is taken, and the existence of
psychiatric or medical comorbidities (122,135,136). Identical twins are highly
concordant in their response to single doses of stimulants, suggesting an
important genetic component. In animals, response to stimulants appears to be
under polygenic control, with independent genetic influences on responses to
cocaine or amphetamine (137). In rats, behavioral response to cocaine shows a
negative correlation with baseline brain dopamine concentrations and a positive
correlation with the increase in dopamine concentration elicited by a cocaine
challenge (138).
Individual differences in tolerance and sensitization to stimulants (see later
discussion: Neuroadaptations) may account for the poor correlation between
stimulant plasma concentrations and toxic effects (122,139,140). Fatal cases of
amphetamine or cocaine intoxication may present with 100-fold differences in
plasma stimulant concentration (11).
Chronic Effects
Chronic cocaine or amphetamine use is associated with cognitive impairment
that may persist for at least several months of abstinence (141,142). Most
affected are visuomotor performance, attention, inhibitory control, and verbal
memory. Several studies have found abnormalities of behavioral regulation and
risk-reward decision-making. This type of impairment is associated with lesions
of the frontal cortex, a brain area that shows decreased regional blood flow and
metabolic activity in abstinent cocaine users.
Chronic cocaine use is associated with decreased gray and white matter
volumes in the frontal cortex of the brain (143), enlarged basal ganglia, and
lower concentrations of N-acetylaspartate (a magnetic resonance spectroscopy
marker for normal neuronal function) and higher concentrations of creatine and
myoinositol (markers of glial cell activity and inflammation) (144).
Chronic amphetamine or methamphetamine use (either oral or intravenous)
can cause a psychotic syndrome (with paranoia and hallucinations) that may
persist for years after the last drug use, even in persons with no personal or
family history of psychiatric disorder (145,146). Methamphetamine psychosis
may be associated with focal perfusion deficits in the frontal, parietal, and
temporal lobes of the cerebral cortex (147). Psychotic flashbacks have been
reported in methamphetamine users up to 2 years after their last drug use and
often are precipitated by threatening experiences (146). A persisting psychosis
after cocaine use has not been reported, except in patients with an underlying
psychiatric disorder (such as schizophrenia or bipolar disorder) (148).
Withdrawal
Cessation of heavy and/or chronic stimulant use may result in a withdrawal
syndrome that does not have prominent physiological features and is not life-
threatening (149–151). Withdrawal symptoms generally are the opposite of those
associated with stimulant intoxication and include depressed mood, anhedonia
(inability to experience pleasure), fatigue, difficulty concentrating, increased
total sleep and rapid eye movement sleep duration (but with poor sleep quality)
(152), and increased appetite. An initial period of intense symptoms (often
termed a “crash”) may occur, including psychomotor retardation and severe
depression with suicidal ideation. However, most users experience mild
symptoms that resolve within 1-2 weeks, usually without treatment. Stimulant
withdrawal is rarely medically serious.
Criteria for the psychiatric diagnosis of stimulant withdrawal are given in
Appendix 4. Treatment of stimulant withdrawal is reviewed in Chapter 54,
“Management of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club
Drug Intoxication and Withdrawal.”
The few human studies on cocaine withdrawal do not find consistent
changes in peripheral markers of dopamine activity, as in plasma concentrations
of dopamine metabolites or of prolactin (a hormone under dopamine control)
(153,154). Human brain imaging studies suggest a modest increase in dopamine
transporter binding during early cocaine withdrawal (using single-photon
emission computed tomography [SPECT]) (155), followed by a decrease after
11-30 days of abstinence (using PET) (154). This pattern is consistent with most,
but not all, postmortem studies of cocaine users (156).
Behavioral Pharmacology
Cocaine, amphetamines, cathinone, ephedrine, and most other stimulants that
have been tested in animals consistently produce increased motor activity,
repetitive stereotyped behavior, drug discrimination, and evidence of reinforcing
effects (such as drug self-administration and conditioned place preference)
(157–159). Animals allowed free access to stimulants often self-administer in a
“binge-abstinence” pattern: periods of high levels of drug intake (producing
stereotyped behavior, hyperactivity, decreased eating, and little sleep),
alternating with periods of abstinence, during which behavior returns to normal
(138). Animals given unlimited access to stimulants may self-administer to the
point of death during a binge period. The rewarding effect of stimulants in
animals is influenced by the same factors as are other drug and natural
reinforcers, for example, the dose of drug available, the schedule of
reinforcement, the animal’s past history of development and drug exposure, and
the current environment and condition of the animal. Stimulant self-
administration is reduced by increased work requirements, availability of an
alternative potent reinforcer, or the concurrent presence of punishment (as by
electric shock) and increased by food deprivation or stress (136,160).
Animals undergoing enforced abstinence after a period of stimulant self-
administration initially increase their responding in an apparent attempt to obtain
drug but eventually extinguish their drug-seeking behavior (138). However, they
will promptly resume drug-seeking behavior if given a single “priming” dose of
the drug or exposed to drug-associated stimuli or stress (such as electric foot
shock) (161). This reinstatement of drug-seeking behavior has been considered
an animal model of relapse to drug use after treatment.
Stimulants produce a distinctive set of subjective psychological effects
(including euphoria, drug liking, increased energy, and increased alertness) in
humans under controlled double-blind experimental conditions (158,162). D-
Amphetamine, benzphetamine, cocaine, ephedrine, mazindol, methylphenidate,
phenmetrazine, and phenylpropanolamine are readily distinguished from placebo
or sedative drugs but often are not distinguished from each other when
equipotent doses are given.
Other Central Nervous System Effects

Acute stimulant administration is associated with transient increases in
electroencephalographic (EEG) alpha, beta, and theta activity, which correlate
with the acute psychological effects (163). Case series suggest that stimulant use
by any route of administration can cause seizures (usually single, generalized
tonic–clonic), even in persons without a pre-existing seizure disorder (164).
Most such cocaine-associated seizures occur within 90 minutes of drug use,
during the time of peak plasma concentration. However, a recent systematic
review of 22 cross-sectional and one case–control study did not find cocaine use
a significant risk factor for seizures (165).
Cocaine and amphetamine use are associated with cerebral vasoconstriction,
cerebrovascular atherosclerosis, cerebrovascular disease, and stroke (166,167).
In a study of more than 800,000 discharges from Texas hospitals in 2003,
cocaine and amphetamine users had more than twice the risk of stroke than
patients not using stimulants (168). A systematic review of seven case–control
and two cross-sectional studies found cocaine use significantly associated with
both hemorrhagic stroke (adjusted odds ratios 2-6) and ischemic stroke (adjusted
odds ratio 2) (169). A recent population-based case–control study involving
2244 subjects found past-24-hour cocaine use significantly associated with
stroke (adjusted odds ratio 5.7) (170). An underlying cerebrovascular
abnormality (such as arterial aneurysm or arteriovenous malformation) probably
increases the risk of cocaine-associated stroke, but the majority of such stroke
patients do not have any identified cerebrovascular risk factors. The OTC
stimulant phenylpropanolamine, marketed as a decongestant and appetite
suppressant, was associated with a significant risk of hemorrhagic stroke in a
recent case–control study, even in patients who used recommended doses (171).
This finding led the FDA to remove phenylpropanolamine from the US market
in October 2000.
Stimulant use is associated with a variety of movement disorders,
presumably as the result of increased dopamine activity in the basal ganglia and
other brain areas that control movement (172). Such disorders include repetitive
stereotyped behaviors (such as repeated dismantling of objects, cleaning,
doodling, and searching for imaginary objects), acute dystonic reactions,
choreoathetosis and akathisia (so-called crack dancers), buccolingual dyskinesias
(“twisted mouth” or “boca torcida”), and exacerbation of Tourette syndrome and
tardive dyskinesia. Cocaine users are at increased risk of extrapyramidal
symptoms (but not akathisia) when taking antipsychotic medications (173).
Cardiovascular System
Stimulants act acutely on the cardiovascular system both directly (by increasing
adrenergic activity at sympathetic nerve terminals) and via the CNS to increase
heart rate, blood pressure, and systemic vascular resistance (174,175). Stimulant-
induced increases in heart rate and blood pressure are significantly correlated
with increases in plasma norepinephrine and epinephrine concentrations
(176,177), suggesting mediation by increased activity of the sympathetic
nervous system. The mechanism may be prolonged blockade of norepinephrine
transporters in the heart, amplifying the action of endogenous norepinephrine.
Cocaine-induced tachycardia is blocked by beta-adrenergic receptor
antagonists (propranolol) but not by muscarinic receptor antagonists (atropine)
(178), further suggesting a sympathetic role. The resulting increase in
myocardial oxygen demand, often accompanied by decreased coronary blood
flow (from vasospasm and vasoconstriction), may cause acute myocardial
infarction, even in young persons without atherosclerosis. This process may be
promoted by cocaine-induced increases in circulating activated platelets, platelet
aggregation, and thromboxane synthesis. Cocaine use is a factor in about one-
fourth of nonfatal heart attacks in persons younger than 45 years (179). Frequent
cocaine users are up to seven times more likely to have a nonfatal heart attack
than are nonusers (179).
Cocaine use is associated with cardiac arrhythmias (such as ventricular
tachycardia or fibrillation) and sudden death (174,180). The mechanisms include
blockade of myocyte sodium channels (resulting in impaired cardiac conduction
and areas of localized conduction block) and increased concentration of plasma
norepinephrine (which sensitizes the myocardium).
Chronic cocaine or amphetamine use is associated with cardiomyopathy and
myocarditis (181–184). Case series of asymptomatic persons with a cocaine
addiction have found up to half with echocardiographic abnormalities such as
left ventricular hypertrophy and abnormal segmental wall motion. Cocaine-
associated cases of dilated cardiomyopathy and myocardial fibrosis may be due
to direct toxic effects of high concentrations of circulating norepinephrine.
Cocaine-associated myocarditis (whose acute symptoms may mimic myocardial
infarction) may be a direct toxic effect of cocaine or a hypersensitivity effect.
Autopsy series of current cocaine users have found myocarditis in up to 20%.
Other Organ Systems

No large surveys or prospective studies have comprehensively evaluated the
natural history of stimulant use or the frequency of adverse effects. Existing
knowledge derives largely from case reports or case series of persons who come
to medical attention. In the absence of experimental data, it may be difficult to
determine the extent to which an observed adverse effect is the result of a direct
action on the affected organ or tissue, an indirect action, an effect of a street drug
contaminant, or secondary to other factors that are part of a drug-using lifestyle,
such as needle sharing, malnutrition, use of other substances, and the like. The
most relevant indirect action of cocaine in producing adverse effects in many
organs and tissues is ischemia and infarction. These effects result from several
mechanisms, including vasoconstriction, vasospasm, damage to endothelium,
and increased clotting as the result of increased number of circulating activated
platelets, enhanced platelet aggregation, and increased thromboxane synthesis.
These mechanisms often reinforce one another: for example, vasospasm may
damage endothelium, endothelial damage increases thromboxane synthesis, and
thromboxane causes platelet aggregation and vasoconstriction.
Adverse effects of stimulant use on particular organ systems often depend on
the route of administration. For example, smoked stimulants produce lung
toxicity not found with other routes, injection use is associated with infectious
diseases such as human immunodeficiency virus and hepatitis C, and intranasal
use is associated with damage to the nasal septum.
Pulmonary
Smoked cocaine produces both acute and chronic pulmonary toxicity (185–187).
Acute respiratory symptoms may develop in up to half of users within minutes to
several hours after smoking. Symptoms include productive cough, shortness of
breath, wheezing, chest pain, hemoptysis, and exacerbation of asthma. More
severe, and rarer, acute effects include pulmonary edema, pulmonary
hemorrhage, pneumothorax, pneumomediastinum, and thermal airway injury.
Pulmonary edema also has been reported after intravenous cocaine use. Chronic
cocaine smoking has been associated in case reports with pulmonary and
peripheral eosinophilia, interstitial pneumonitis, and bronchiolitis obliterans. The
pathophysiology of these adverse effects is not definitively understood but
presumably involves a combination of direct damage by cocaine or inhaled
microparticles to the alveolar capillary membrane, vasoconstriction and damage
to the pulmonary vascular bed, and/or interstitial disease.
The long-term effect of cocaine smoking on pulmonary function remains
unclear (187). Standard pulmonary function tests (spirometry) have been normal
in most studies. Some studies have found increased alveolar epithelial
permeability and moderately decreased (up to 20%) pulmonary diffusion
capacity among cocaine smokers without acute symptoms, although other
studies have found normal function. The attribution of these abnormalities to
cocaine use is confounded by the fact that the vast majority of cocaine-smoking
subjects also were smokers of tobacco and/or marijuana.
Renal
Stimulants have little direct toxic effect on the kidneys. Acute renal failure can
occur as a result of renal ischemia or infarction, malignant hypertension, or
rhabdomyolysis (see later discussion: Musculoskeletal) (188,189). Release of
myoglobin during rhabdomyolysis may cause renal tubular obstruction or direct
myoglobin damage to renal tubules. Intrarenal arterial constriction with resulting
renal medullary ischemia also may contribute to renal tubular damage.
Gastrointestinal
Cocaine reduces gastric motility and delays gastric emptying, in part by affecting
medullary centers that regulate these functions. The major gastrointestinal
effects of cocaine use are due to vasoconstriction and ischemia: gastroduodenal
ulceration and perforation, intestinal infarction and perforation, and ischemic
colitis (190,191). The distribution of cocaine-associated ulcers is primarily in the
greater curvature and prepyloric region of the stomach, pyloric canal, and first
portion of the duodenum, whereas peptic ulcers occur primarily in the duodenal
bulb. Concealing cocaine by swallowing large packets (“body packing”) may
result in severe acute toxicity if the wrapping deteriorates and allows cocaine
into the gastrointestinal tract (75).
Liver
Cocaine is hepatotoxic in rodents, presumably because of oxidative metabolism
to norocaine by the cytochrome P450 microsomal enzyme system in the liver,
with further transformation to reactive hepatotoxic compounds such as N-
hydroxy-norcocaine (192). This is a very minor metabolic pathway in humans
(see previous discussion: Metabolism). There is no direct evidence that cocaine
is hepatotoxic in humans. Liver abnormalities reported in case series of cocaine
users can be accounted for by viral hepatitis from injection drug use, liver
disease because of alcohol use, rhabdomyolysis, or other consequences of a
drug-using lifestyle (193).
Endocrine
Acute cocaine use activates the hypothalamic–pituitary–adrenal (HPA) axis,
stimulating secretion of epinephrine, corticotropin-releasing hormone (CRH),
ACTH, and cortisol (194). Acute cocaine use decreases plasma prolactin
concentrations in cocaine-naive individuals, presumably because of increased
dopamine activity (dopamine inhibits prolactin release from the pituitary).
Chronic cocaine users may have increased, normal, or decreased prolactin levels
and usually do not show changes in response to acute cocaine. Acute cocaine use
increases plasma luteinizing hormone, but chronic cocaine users have normal
levels of testosterone, cortisol, luteinizing hormone, and thyroid hormones. A
blunted thyroid-stimulating hormone response to thyroid-releasing hormone
stimulation has been reported in one study but has not been replicated. Cocaine
use is associated with increased risk of diabetic ketoacidosis, either because of
poor treatment adherence or acute stimulation of the HPA axis (195).
Musculoskeletal
Stimulants may cause rhabdomyolysis by several different mechanisms: a direct
toxic effect causing myofibrillar degeneration (probably rare except at very high
doses), indirectly by vasoconstriction of intramuscular arteries resulting in
ischemia, and secondary to stimulant-induced hyperthermia or seizures
(190,196). Up to one-third of patients with rhabdomyolysis will develop acute
renal failure, sometimes accompanied by disseminated intravascular coagulation
and liver damage. This syndrome often is fatal.
Head and Neck

Common head and neck complications of cocaine use depend on the route of
administration. Intranasal cocaine use (“snorting”) is associated with chronic
rhinitis, perforated nasal septum and nasal collapse, oropharyngeal ulcers, and
osteolytic sinusitis, presumably due to vasoconstriction and resulting ischemic
necrosis (197,198). Changes in the sense of smell are rare, even in heavy users
with intranasal damage (199). Oral cocaine use is associated with gingival
ulceration and erosion of dental enamel. In South America, chronic coca leaf
chewing has been associated with mild epithelial changes but no evidence of
premalignant or malignant lesions (200). The observed changes may result from
the alkaline ash usually chewed with the leaves to enhance cocaine extraction
rather than from the cocaine itself. Smoked cocaine (“crack”) may cause corneal
ulcers (201). Use of cocaine or amphetamines by any route of administration
reduces salivary secretions (xerostomia) and causes bruxism (202). Chronic use
is associated with several dental problems, including caries, cracking of tooth
enamel, and loss of teeth (“meth mouth”). Because oral health problems are
pervasive among stimulant users, dental professionals serve an important role in
identifying these users and getting them into treatment.
Immune System
Cocaine use has been associated with a variety of vasculitic syndromes primarily
affecting the skin and muscle (203). These may mimic rheumatological
conditions such as Henoch-Schönlein purpura, Steven-Johnson syndrome, or
Raynaud phenomenon. Cocaine-associated midline destructive lesions may
resemble Wegener granulomatosis (204). In experimental studies, cocaine
impairs innate immune mechanisms (eg, the response of monocytes to bacterial
lipopolysaccharide) (205).
Sexual Function
Stimulants are commonly thought of as an aphrodisiac, but chronic use usually
reduces libido and impairs sexual function (206–208). Men may experience
erectile dysfunction or delayed or inhibited ejaculation. Priapism is rare. Women
may develop irregular menses. Cocaine has been applied to the penis or clitoris
to use its local anesthetic effect to delay organism (206).
Reproductive, Fetal, and Neonatal Health
Prescription stimulants, including cocaine and amphetamines, are classified by
the FDA in pregnancy category C, meaning that risk cannot be ruled out because
human studies are lacking. One exception is diethylpropion, which is category B
(no evidence of risk in humans). Male chronic cocaine users have reduced sperm
count and motility (207).
Prenatal (in utero) exposure to cocaine, amphetamines, or methylphenidate
has been associated with vaginal bleeding, abruptio placenta, placenta previa,
premature rupture of membranes, decreased head circumference, low birth
weight, tremulousness, irritability, poor feeding, and autonomic instability (209).
It is usually difficult in these studies to distinguish a direct effect of the stimulant
from the effects of concomitant factors frequently present in people who use
drugs, such as other substance use (including alcohol, nicotine, and opioids),
poor nutrition, and lack of prenatal care. Long-term studies suggest that prenatal
cocaine exposure is associated with small but statistically significant
impairments in sustained attention and behavioral self-regulation among
preschool- and school-aged children (210) and in language and memory among
adolescents (211). These effects appear modifiable by environmental factors
such as prenatal care and the care-giving environment. Their causal mechanisms
remain unknown. Cocaine, amphetamines, phentermine, ephedrine, and
pseudoephedrine appear in breast milk (110). Cocaine and amphetamines may
cause irritability, sleep disturbance, and tremors in the infant. Medical use by the
mother of other prescription and OTC stimulants in appropriate doses usually
does not have clinically significant adverse effects on nursing infants.
NEUROBIOLOGY
Mechanisms of Action
Molecular mechanisms
All stimulant drugs act to enhance extracellular concentrations of monoamine
neurotransmitters, chiefly the catecholamines dopamine and norepinephrine, in
the central and peripheral nervous systems. Stimulants achieve their effects by
disrupting the function of plasma membrane transporter proteins expressed on
neurons that synthesize and release these neurotransmitters (212) (Fig. 12-3).
Under normal circumstances, monoamine transporters mediate the uptake (or
reuptake) of previously released neurotransmitter molecules from the
extracellular space back into nerve cells, thus terminating neurotransmitter
action. Monoamine transporters belong to a gene family of neurotransmitter-
sodium transporters, which depend upon intact sodium gradients to facilitate
neurotransmitter uptake. Because transporters are not confined to nerve endings
(ie, synapses), being also found on cells bodies, dendrites and axons, they are
critically involved with controlling extrasynaptic volume transmission of
monoamines (213).
Figure 12-3 Mechanism of action of stimulants acting as

monoamine transporter blockers (A) or substrates (B). Drugs
that act as monoamine transporter (MAT) blockers increase
the concentration of amine neurotransmitters (ie, dopamine,
norepinephrine, and serotonin) in the extracellular fluid
(ECF) by blocking reuptake of previously released
neurotransmitter molecules. Drugs that act as MAT substrates
increase concentrations of amine transmitters in the ECF by a
two-pronged mechanism: (a) they promote nonexocytotic
release of cytoplasmic amine transmitters by entering neurons
and reversing the normal direction of transporter flux (ie,
reverse transport), and (b) they disrupt storage of transmitters
in vesicles by interacting with vesicular monoamine
transporters (VMATs). The disruption of transmitter storage
increases cytoplasmic concentration of transmitter molecules
available for transporter-mediated release.
Stimulant drugs can be divided into two classes based on their molecular
mechanism of action: transporter blockers (see Fig. 12-3A) and transporter
substrates (see Fig. 12-3B; Table 12-4). Transporter blockers, like cocaine and
methylphenidate, bind to the extracellular face of transporters and inhibit the
uptake of previously released monoamine neurotransmitters. Thus, transporter
blockers are often called uptake or reuptake blockers. Transporter substrates, like
amphetamine and phentermine, have a more complex mechanism of action
(214). These drugs bind to transporters, are transported into the neuronal
cytoplasm along with sodium ions, and trigger release of intracellular
monoamines by reversing the normal direction of transporter flux. Once inside
the neuronal cytoplasm, transporter substrates interact with vesicular monoamine
transporters (VMATs) to disrupt monoamine storage, thereby greatly increasing
cytoplasmic concentrations of amines available for release. Because transporter
substrates elicit transmitter efflux by reverse transport, they are sometimes
referred to as releasers.
TABLE 12-4 Neuropharmacological Actions of Selected

Stimulants
aAlso direct agonist at adrenergic (norepinephrine) receptors.

MAO, monoamine oxidase; 0, no effect; +, marginal effect; ++, substantial effect; +++, predominant
effect.
Based on data from Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine-type central nervous
system stimulants release norepinephrine more potently than they release dopamine and serotonin.
Synapse. 2001;39(1):32-41; Howell LL, Kimmel HL. Monoamine transporters and psychostimulant
addiction. Biochem Pharmacol. 2008;75(1):196-217.
Potent stimulants like cocaine and amphetamine are active at dopamine and
norepinephrine transporters, whereas weaker stimulants like (−)-ephedrine and
its isomers preferentially target norepinephrine transporters (215,216). Drugs
that selectively interact with serotonin transporters are generally not perceived as
stimulant-like and are not addictive (eg, serotonin selective reuptake inhibitors,
SSRIs). Many stimulant drugs also have nontransporter sites of action that
contribute to their pharmacological effects. For example, cocaine blocks sodium
channels and amphetamines inhibit monoamine oxidase. Ephedrine,
pseudoephedrine, phenylephrine, and phenylpropanolamine are weak agonists at
alpha-adrenergic receptors, which mediate vasoconstriction (hence their use as
decongestants and antihypotensive agents). Ephedrine also has some action at
beta-adrenergic receptors, which mediate bronchodilation.
Neural Circuits and Systems

Animal studies demonstrate that rewarding effects of stimulants and other
addictive substances are mediated by activation of the mesocorticolimbic
dopamine system (217). In the rat, this pathway consists of cells bodies in the
ventral tegmental area (VTA) that send axonal projections to the prefrontal
cortex (PFC), nucleus accumbens, and amygdala. Distinct subpopulations of
VTA dopamine neurons are associated with projection-specific functional roles
in mediating reward, aversion, and stress (218). Mesocorticolimbic dopamine
neurons are part of a complex cortical–striatal–pallidal circuitry that is involved
with the selection of adaptive behavioral responses (219). The nucleus
accumbens is a critical node in the circuitry, receiving stimulatory glutamate
afferents from hippocampus, amygdala, and frontal cortex. The primary cell type
in the nucleus accumbens is the GABA-containing medium spiny neuron, which
receives direct synaptic contacts from both dopamine and glutamate inputs.
Medium spiny neurons send efferent projections to a variety of targets, including
pallidal structures (eg, substantia nigra pars reticulata), which are involved in
tonic suppression of motor nuclei. Thus, activation of GABAergic medium spiny
neurons can recruit motor behaviors by inhibiting pallidal output (ie, via
disinhibition).
Medium spiny neurons can be divided into two types based on phenotype
(and other factors): neurons expressing low-affinity D1 dopamine receptors and
those expressing high-affinity dopamine D2 receptors (220). Medium spiny
neurons require glutamate stimulation to drive their activity; dopamine receptors
differentially modulate responsiveness to glutamate input. In general, activation
of D1 receptors increases excitability of medium spiny neurons (ie, so-called up
state), making them more receptive to glutamate stimulation, whereas activation
of D2 receptors has the opposite effect. Under basal resting conditions, when
extracellular dopamine levels are low, high-affinity D2 receptors inhibit activity
of spiny neurons, and behavior is suppressed. When dopamine levels are
increased, activation of low-affinity D1 receptors facilitates excitation of spiny
neurons, and behavior is executed. Natural rewards induce transient, localized
changes in extracellular dopamine in nucleus accumbens (via VTA cell firing)
that are capable of modulating stimulatory drive in discrete populations of
medium spiny neurons. By contrast, stimulant drugs induce sustained
supraphysiological elevations in extracellular dopamine that cause widespread
excitation of medium spiny neurons, and repeated drug exposure changes circuit
function.
The nucleus accumbens and PFC are the key sites for stimulant reward
(138). In rodents, selective dopamine lesions or administration of dopamine
receptor blockers in the nucleus accumbens, but not in other sites, abolish the
rewarding effects of cocaine or amphetamine. Rodents will self-administer
amphetamine directly into the nucleus accumbens or PFC and cocaine directly
into the PFC, but not into other brain sites. Cocaine administration into the PFC
increases dopamine turnover in the nucleus accumbens. The relationship
between cocaine self-administration and extracellular dopamine concentration in
the nucleus accumbens also suggests a key role for this site (138). A period of
cocaine self-administration increases tonic concentrations of extracellular
dopamine, with each individual dose producing a time-locked phasic increase.
The subsequent decline in dopamine concentration predicts the self-
administration of the next dose. Overall, the animal appears to be titrating
extracellular dopamine concentration in the nucleus accumbens to maintain an
increase above baseline concentration.
The evidence for brain localization of stimulant effects in humans is limited
but somewhat consistent with the animal studies. Brain imaging studies using
PET, SPECT, or functional magnetic resonance imaging have found stimulant-
induced changes in blood flow or metabolic rate in a variety of brain regions,
including frontal cortex, anterior cingulate, ventral striatum (which includes the
nucleus accumbens), and amygdala (221). Exposure to cocaine-associated
stimuli that elicit cocaine craving is associated with increased blood flow or
metabolic activity in the PFC, amygdala, and anterior cingulate gyrus.
Dopamine
Cocaine, amphetamines, methylphenidate, and modafinil enhance dopamine
transmission by acting at dopamine transporters, as described earlier (see Table
12-4). The cocaine- binding site on the dopamine transporter overlaps with the
binding sites for dopamine and amphetamine (222). Acute administration of
cocaine or amphetamine transiently increases brain extracellular dopamine
concentrations in animals and humans, especially in the striatum (which includes
the nucleus accumbens) (223). Repeated administration of cocaine or
amphetamine increases D1 receptor sensitivity in the nucleus accumbens but has
variable effects on other dopamine receptor measures (224).
Several lines of evidence from animal studies show that increased synaptic
dopamine activity in the mesocorticolimbic reward circuit mediates the
behavioral effects of stimulants (215). In rats, the magnitude of locomotor
activation produced by methamphetamine and other stimulants is positively
correlated with extracellular concentrations of dopamine in the nucleus
accumbens (225). Fluctuations in extracellular dopamine and neuronal firing in
the nucleus accumbens parallel cocaine self-administration (226). The potency
of cocaine analogues and other stimulants for being self-administered or
producing cocaine-like discriminative stimuli is highly correlated with their
affinity for and speed of binding to the dopamine transporter (227), but not with
their binding to other monoamine transporters or receptors (228). Conversely,
lesions of dopamine neurons in the reward circuit (but not other brain regions)
reduce cocaine self-administration (229). Mice genetically engineered to express
functional dopamine transporters without a cocaine-binding site do not show
reinforcing or other behavioral effects of cocaine (230–233).
Dopamine D1 and D2/D3 receptors appear to play reciprocal roles in the
behavioral effects of stimulants (224). Blockade of D1 receptors in regions of the
brain reward circuit (eg, the shell of the nucleus accumbens or VTA) reduces the
rewarding effects of cocaine or amphetamine in the rat, as does stimulation of D3
receptors (234,235). Knockout mice that lack the D1 receptor do not self-
administer cocaine (236), whereas D3 knockout mice show enhanced responses
to cocaine or amphetamine (237). In vivo calcium imaging studies, carried out in
transgenic mice expressing fluorescent proteins to label defined cell types, show
that psychomotor stimulant effects of cocaine are accompanied by rapid
activation of D1 receptors on striatal medium spiny neurons, followed by slower
more persistent deactivation of D2 receptors in the same region (238).
Evidence from human brain imaging studies using PET or SPECT is largely
consistent with an important role for dopamine in the acute psychological effects
of stimulants. The acute positive psychological response (euphoria or “high”) to
cocaine or methylphenidate correlates in time course and intensity with drug
concentration in the brain, with dopamine transporter occupancy (in the case of
cocaine) (228), and with extracellular dopamine release in the striatum (as
measured by ligand displacement from dopamine receptors) (222,223). Exposure
to cocaine-associated cues is also associated with dopamine release in the
striatum; the degree of release is correlated with cocaine craving (223). Blockade
of more than half the dopamine receptors is needed to reduce cocaine self-
administration in animals (228) or reduce the subjective effects in humans.
Some clinical evidence does not support a role for dopamine activity in
stimulant effects. For example, patients with schizophrenia taking first-
generation antipsychotics (which are potent dopamine D2 receptor antagonists)
at doses that control their schizophrenic symptoms still experience the
psychoactive effects of cocaine and frequently use it recreationally (239).
Experimental attempts to block the acute psychological effects of cocaine or
amphetamine with antipsychotic medication or by blocking dopamine and
norepinephrine synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-p-
tyrosine have not been successful (240–242). The failure of antipsychotics to
block effects of cocaine could be due to lack of D1 receptor antagonism by these
medications or the inability of subjects to tolerate sufficient doses of medication
to influence cocaine’s effects.
Postmortem studies of human brain suggest that cocaine users have
decreased dopamine levels in the frontal cortex (243), normal levels of dopamine
receptor binding (244), decreased VMAT in striatum (245), and decreased
transporter protein and messenger RNA levels (156,246,247). In vivo human
studies using PET show that cocaine users have decreased dopamine D2 receptor
binding in striatum and frontal cortex, which may persist for months of
abstinence, but normal levels of dopamine transporter binding (223,248,249).
Cocaine-addicted subjects also display blunted dopamine release in response to
amphetamine challenge, suggesting a presynaptic dopamine deficiency (249). In
contrast, methamphetamine users have increased D1 receptors in the nucleus
accumbens (250) and decreased dopamine transporter density in nucleus
accumbens, striatum, and PFC (251). Reductions in dopamine transporter
number in the brains of methamphetamine users could reflect neurotoxic loss of
dopamine nerve terminals.
Norepinephrine
Cocaine, amphetamines, methylphenidate, phentermine, and ephedrine enhance
norepinephrine neurotransmission by acting at norepinephrine transporters (see
Table 12-4), but the importance of norepinephrine in mediating behavioral
effects of cocaine is not well understood. Intravenous cocaine increases plasma
norepinephrine and epinephrine concentrations within minutes of injection,
probably due to blockade of norepinephrine transporters on peripheral
sympathetic nerve terminals (176). There is a significant positive correlation
between potency of norepinephrine release (measured in vitro) and the oral
stimulant dose that produces stimulant like subjective effects in humans,
suggesting a role for norepinephrine in the psychological effects of stimulants
(252). Chronic cocaine exposure increases norepinephrine transporter function in
monkey and human brain (229,253).
Evidence supports a modulatory role for specific norepinephrine receptor
subtypes in the effects of cocaine and other stimulants. Blockade of alpha-1
adrenergic receptors attenuates locomotor effects of stimulants in rats (254) and
blunts the subjective effects of cocaine in human drug users (255). Activation of
alpha-2 adrenergic receptors with clonidine reduces stress-induced reinstatement
of extinguished cocaine seeking in rats (256) and drug craving in abstinent
cocaine-dependent human subjects (257). The therapeutic effects of alpha-2
agonists in cocaine addiction are most likely related to activation of presynaptic
autoreceptors on norepinephrine cells, which serve to dampen norepinephrine
cell firing and transmitter release.
Serotonin
Most stimulant drugs exhibit lower potency at serotonin transporters than at
catecholamine transporters (see Table 12-4). Cocaine is an exception, as it blocks
uptake at transporters for serotonin, dopamine, and norepinephrine with
comparable potency. Acute cocaine administration increases extracellular
serotonin concentrations in the nucleus accumbens and VTA and reduces firing
of serotonin neurons in the dorsal raphe. The latter action probably is mediated
by negative feedback from stimulation of 5-HT1A autoreceptors (258).
The role of serotonin in stimulant reward in animals is unclear. Knockout
mice lacking the serotonin transporter still find cocaine rewarding (self-
administration, conditioned place preference), whereas double knockout mice
lacking both the dopamine and serotonin transporters do not (259). Knockout
mice lacking both the norepinephrine and serotonin transporters show increased
sensitivity to cocaine reward. These findings suggest a permissive, but not
obligatory, role for the serotonin transporter in cocaine reward.
Determining the importance of serotonin receptors in mediating effects of
cocaine is complicated by the presence of more than a dozen receptor subtypes,
which can differentially influence cocaine-induced behavior (260). Activation of
5-HT1A, 5-HT1B, 5-HT2A, or 5-HT3 receptors enhances the locomotor and
rewarding actions of cocaine, whereas activation of 5-HT2C receptors reduces
the effects of cocaine and other stimulants. 5-HT2A antagonists and 5-HT2C
agonists exert similar inhibitory modulation of cocaine’s effects. The 5-HT2A
antagonist M100907 and 5-HT2C agonist Ro60-0175 attenuate reinstatement of
extinguished cocaine-seeking behavior produced by priming injections of
cocaine or cue exposure (261). These same drugs inhibit the premature
responding produced by cocaine and amphetamine in the 5-choice serial reaction
test, a measure of impulsive action (262). Microinjection studies reveal that 5-
HT2A receptors in VTA and 5-HT2C receptors in the PFC could be involved with
the effects of serotonergic receptor drugs on cocaine-induced behaviors (263).
Human studies using nonselective serotonin manipulations provide an
inconsistent picture of the influence of serotonin on cocaine reward.
Enhancement of synaptic serotonin activity with selective serotonin reuptake
inhibitors, activation of serotonin receptors with a partial agonist, or depletion of
serotonin levels (via a tryptophan-free diet) all are reported to reduce the acute
subjective effects (“high,” craving) of cocaine (264,265). Neuroendocrine
challenge studies in cocaine-addicted human subjects show that hormonal
responses to serotonin releasers (fenfluramine) and serotonin receptor agonists
(mCPP) are blunted during withdrawal (266,267). These findings suggest that
chronic cocaine use engenders deficits in serotonergic transmission, which is
consistent with symptoms of depression and negative affect experienced by
withdrawn cocaine-addicted subjects (268). The clinical availability of receptor-
selective agonists and antagonists will aid in determining the role of serotonin in
stimulant reward.
Endogenous Opioids
Stimulants do not directly interact with opioid receptors but do influence
endogenous opioid (endorphin, enkephalin) systems in the brain. In rats, single
doses of cocaine or amphetamine increase extracellular endorphin levels in the
nucleus accumbens and enkephalin and dynorphin mRNA levels in striatum
(269,270). The mechanism is indirect, via other neurotransmitters, especially
dopamine, that influence endogenous opioid release.
Repeated cocaine administration, especially in an intermittent binge pattern,
increases brain mu and kappa opiate receptor binding in rodents, with no change
in delta opioid receptors (271). Human cocaine users show increased mu opioid
receptor binding in some brain regions with PET scanning, and this increased
binding correlates with self-reported cocaine craving (272). Postmortem brains
from fatal cocaine overdose victims show increased kappa opioid receptor
binding in limbic areas (273).
Animal studies suggest that brain kappa opioid systems have an influence on
cocaine effects. In general, activation of endogenous kappa opioid receptor
systems (such as by administration of the endogenous ligand dynorphin) reduces
behavioral and neuropharmacological effects of stimulants (274).
Glutamate
The acute administration of cocaine or amphetamine increases glutamate release
in the VTA, nucleus accumbens, dorsal striatum, ventral pallidum, septum, and
cerebellum (275). Low doses of cocaine enhance glutamate-evoked neuronal
firing and have variable effects on the different subtypes of glutamate receptors.
Several glutamate receptor subtypes appear to play an important role in cocaine
reinforcement. Blockade of N-methyl-D-aspartate receptors in the nucleus
accumbens reduces cocaine reinforcement, as does reduction of mGluR5
receptor activity. Indirect reduction of glutamate activity by stimulating
presynaptic mGluR2 receptors also reduces cocaine reinforcement, whereas
inhibiting mGluR2 activity enhances reinforcement.
A growing body of evidence from rat studies suggests that chronic treatment
with noncontingent or self-administered cocaine produces changes in nucleus
accumbens glutamate transmission, which persist for weeks after cessation of
cocaine exposure (276). For instance, chronic cocaine treatment is accompanied
by a marked decrease in nonsynaptic extracellular glutamate levels, due to a
reduction in cysteine-glutamate exchange. Cocaine-induced decreases in
accumbens glutamate levels may be involved in drug-seeking behavior because
treatment with the prodrug N-acetylcysteine restores extracellular glutamate to
normal levels and attenuates reinstatement of extinguished cocaine-seeking
behavior (277). Withdrawal from chronic cocaine decreases membrane
excitability in GABA-containing medium spiny neurons, which in turn induces a
persistent up-regulation of AMPA-type glutamate receptors on these cells (278).
Up-regulation of AMPA receptors renders medium spiny neurons more receptive
to glutamate inputs from the cortex and other regions. Enhanced glutamate
responsiveness in mesolimbic circuits could underlie stronger responding to
drug-associated cues (279).
Acetylcholine
Cocaine and methamphetamine block neuronal nicotinic acetylcholine (ACh)
receptors; cocaine also blocks muscarinic ACh receptors in the brain and on
cardiac myocytes (280,281). Cocaine, amphetamine, and methamphetamine
cause ACh release in several brain regions, including the striatum, nucleus
accumbens, medial thalamus, and interpeduncular nucleus (281–283). Chronic
cocaine exposure appears to cause down-regulation of brain cholinergic systems,
reflected in decreased choline acetyltransferase activity and decreased nicotinic
receptors. In contrast, chronic methamphetamine exposure appears to result in
increased nicotinic receptor density (280).
Cholinergic receptors may play a role in cocaine reward. Nicotinic ACh
receptors potently regulate dopamine release in the striatum (284), so that
cocaine’s blockade of these receptors alters dopamine release characteristics
(285), which may influence cocaine’s behavioral effects. Rodents with reduced
muscarinic receptor activity show decreased cocaine self-administration and
conditioned place preference (286,287). Nicotinic receptor blockade has variable
effects, depending on the receptor subtype and brain region (288). Enhancing
cholinergic activity by inhibiting acetylcholinesterase (the enzyme that breaks
down ACh) reduces the behavioral effects of cocaine but has no effect on those
of methamphetamine (289,290).
Other Actions
Some stimulants have additional neuropharmacological actions (see Table 10-4).
Amphetamines and phentermine inhibit monoamine oxidase, which also would
increase catecholamine activity. This action probably is not significant at the
drug concentrations achieved with typical therapeutic or abused doses (291).
Cocaine is unique in also blocking voltage-gated membrane sodium ion
channels. This action accounts for its effect as a local anesthetic and may
contribute to cardiac arrhythmias.
Signal Transduction
When monoamine neurotransmitters such as dopamine activate their membrane
receptors on the nerve cell surface, they trigger a cascade of intracellular
chemical events (292). The neurotransmitter receptors are coupled to G-proteins,
which regulate adenylyl cyclase activity to alter levels of cyclic 3′,5′-adenosine
monophosphate (cAMP), an intracellular “second messenger.” Cyclic AMP, in
turn, regulates the activity of protein kinases, phospholipases, and other
intracellular enzymes. These enzymes regulate various intracellular processes,
including the activity of transcription factors that regulate gene transcription by
binding to specific DNA sequences in the regulatory regions of genes (see
further: Gene Expression). Stimulants activate several signaling pathways in
neurons of the brain reward circuit, including cAMP, extracellular signal-
regulated kinase, mitogen-activated protein kinase, and phosphoinositide 3-
kinase, as well as altering expression of proteins that regulate G protein
signaling. Direct manipulation of steps in these pathways can modify stimulant-
induced behavior (293,294). Changes to these pathways from chronic exposure
to stimulants may mediate tolerance and sensitization (see further:
Neuroadaptation).
Gene Expression
Acute administration of stimulants (such as cocaine, amphetamine, and
methylphenidate) to rodents promptly activates several “immediate early” genes
in the brain, such as cAMP response element-binding protein (CREB), c-fos,
zif268, and c-jun, probably via activation of dopamine receptors (295). The
protein products of these genes are nuclear transcription factors that regulate
gene expression. Repeated administration of stimulants results in a long-lasting
blunting of the gene activation effect in many brain regions. Chronic stimulant
administration leads to accumulation of some transcription factors, which may
mediate the development of sensitization (see further: Neuroadaptation).
In animal studies, acute or chronic stimulant administration results in
changes in expression of a variety of genes in many brain regions related to
addiction, including genes involved in neuronal growth, cytoskeletal structure,
synaptic plasticity, and receptors and signal transduction (296). Human
postmortem studies of chronic cocaine users do not always find the same
changes. Genes significantly up-regulated in human studies include cocaine- and
amphetamine-related transcript, CREB, and several glutamate receptor subunits,
whereas several myelin-related genes were down-regulated.
Neuroadaptation
Repeated exposure to stimulants results in two distinct neuroadaptations:
sensitization (increased drug response) and tolerance (decreased drug response)
(297,298).
Behavioral sensitization has two temporally distinct phases: initiation or
induction and expression (298). A combination of environmental and
pharmacological factors influences both phases. Sensitization may be influenced
by circadian rhythm (299) and by the animal’s prior drug experience in the
environment in which the drug is administered (so-called “context-specific” or
“conditioned” sensitization). Behavioral sensitization to stimulants is due, in
part, to increased activity in glutamatergic pyramidal neurons in the medial PFC,
which project to the nucleus accumbens and VTA (300). This increased
excitatory input makes the dopaminergic neurons in these regions more
responsive to stimulation.
Behavioral sensitization to stimulants has been suggested as a mechanism
for drug craving and relapse (301) and for stimulant-induced psychosis (302).
Neither has been directly demonstrated in humans. Several retrospective
evaluations of patients presenting with stimulant-induced psychosis found that
psychotic symptoms were more severe than during prior episodes of use or were
elicited at lower doses that previously had not caused such symptoms (302). This
pattern is consistent with sensitization (ie, an enhanced response to the drug after
prior exposure).
Attempts to demonstrate sensitization prospectively in humans have yielded
inconsistent results (303). Studies using intravenous, intranasal, or oral cocaine
in experienced cocaine users failed to show sensitization after one to several
prior cocaine doses. However, one study using oral cocaine did find significant
sensitization to cocaine’s cardiovascular effects but not to its psychological
effects (304). Studies using oral amphetamines in subjects with little or no prior
stimulant exposure have shown sensitization to psychological and physiological
(eye blink rate) responses after one to three prior oral amphetamine doses. This
sensitized response was still present 1 year after the last amphetamine dose and
included increased dopamine release in the ventral striatum (measured by PET
scanning) (305). The failure to show sensitization in other studies may have been
due to the substantial prior stimulant exposure of most subjects, resulting in
sensitization already having occurred (ie, a “ceiling” effect).
Tolerance to the behavioral (including reinforcing and appetite-suppressing)
effects of stimulants has been demonstrated in animals after high-dose, frequent,
or continuous administration (122,298,306,307). Tolerance to cardiovascular,
hyperthermic, and lethal effects occurs even more quickly, sometimes after just
one or two exposures (122,308). Stimulant tolerance dissipates after 7-14 days of
no exposure (306–308). There is significant cross-tolerance among various
stimulants, but not between stimulants and other drug groups, such as opiates
(309).
Stimulant tolerance is pharmacodynamic (ie, due to adaptive changes in the
brain) rather than pharmacokinetic; chronic stimulant exposure does not cause
substantial changes in stimulant pharmacokinetics (306). Development of
behavioral tolerance is associated with attenuation of the dopamine response to
stimulants, decreased activation of immediate early genes, and increased activity
of the signal transduction pathway involving protein kinase A and the gene
transcription factor CREB (306).
In clinical use, tolerance to stimulants develops differentially to various
effects. Patients typically become tolerant to the appetite-suppressing effects
within several weeks of daily use, whereas the beneficial effects in narcolepsy or
ADHD remain over months of treatment (122,125). In human laboratory studies,
tolerance to psychological, cardiovascular, and neuroendocrine effects of cocaine
and amphetamines may develop after several doses (310–312). There is some
evidence that tolerance to cardiovascular effects develops more quickly and
completely than does tolerance to psychological effects (312,313). Rapid
tolerance to adverse effects presumably allows binge users to take large
cumulative doses of stimulants (314).
Neurotoxicity
In animal studies, transporter blockers like cocaine and methylphenidate do not
produce appreciable neurotoxicity of dopamine or serotonin neurons (315). In
contrast, high doses of transporter substrates like amphetamine or
methamphetamine produce substantial dopamine and serotonin neurotoxicity,
probably because these drugs enter nerve terminals and increase production of
reactive oxygen species (316). Such neurotoxicity in human users has not been
conclusively demonstrated. Chronic methamphetamine or methcathinone users
have reduced density of dopamine transporters in the brain (measured by PET
scanning) for at least 3 years after last use (317), but there is evidence of
recovery after a year of abstinence (318). Thus, it is not clear whether the loss of
transporters represents a reversible physiological response (down-regulation) to
chronic stimulant exposure or a true loss of dopamine nerve endings.
Postmortem brain studies in persons with methamphetamine addiction are more
consistent with the former alternative. Their findings of decreased dopamine
synthesis and dopamine transporter function, but intact vesicular transporter
function, suggest that dopamine nerve terminals and the intracellular storage
vesicles they contain remain intact (32).
Cocaine has caused DNA synthesis inhibition and cell death of brain neurons
in rodents (319), but the clinical relevance of these findings is unknown.
FUTURE RESEARCH DIRECTIONS

Future research at both preclinical and clinical levels is needed to increase
understanding of the mechanisms of stimulant addiction and to develop more
effective prevention and treatment approaches. Productive areas for preclinical
research include the neurochemical mechanisms that underlie stimulant
sensitization and tolerance, the role of non–dopamine neurotransmitter systems
(eg, glutamate, neuropeptides) in modulating the dopamine reward circuit, the
molecular mechanisms underlying stimulant interactions with transporter
proteins, and the role of various genes and gene transcription factors in stimulant
action.
Productive areas for clinical research include the genetic, hormonal,
psychological, and environmental factors that influence response to stimulants
and the progression to stimulant addiction and the development of effective
treatments for stimulant addiction and its medical consequences.
ACKNOWLEDGMENT
Dr. Baumann is supported by the Intramural Research Program, National
Institutes of Health, National Institute on Drug Abuse.
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CHAPTER 13
The Pharmacology of Caffeine
Mary M. Sweeney, Laura M. Juliano, Sergi Ferré, and
Roland R. Griffiths
CHAPTER OUTLINE
Introduction
Drugs in the Class
History
Epidemiology
Sources of Caffeine
Therapeutic Uses
Neurobiology
Pharmacokinetics
PhysiologicAL Effects
Subjective Effects
Performance Effects
Reinforcing Effects
Caffeine Tolerance
Caffeine Intoxication
Caffeine Withdrawal
Caffeine Use Disorder
Genetics
Effects on Physical Health
INTRODUCTION
Caffeine is the most widely used mood-altering drug in the world. Caffeine is a
nonselective A1 and A2A adenosine receptor antagonist and mild central nervous
system (CNS) stimulant. Moderate caffeine consumption is not generally
associated with negative health effects. Moreover, caffeine has valuable
therapeutic effects and may offer protective effects from some diseases.
However, caffeine has the potential to produce clinically significant negative
physiological and psychological effects, tolerance and withdrawal, and
psychiatric disorders. Furthermore, its use in combination with recreational and
psychotherapeutic drugs can have important clinical implications. The
ubiquitous use of caffeine may make the recognition and treatment of caffeine-
associated problems particularly challenging.
DRUGS IN THE CLASS
Caffeine is the common name for 1,3,7-trimethylxanthine (Fig. 13-1). More than
60 types of plants contain caffeine, including coffee, tea, cola, guarana, cacao,
and yerba maté. Caffeine is a member of the methylxanthine class of alkaloids,
which includes the structurally related dimethylxanthines, theophylline, and
theobromine. Caffeine in its free base form is a bitter white powder that is
moderately soluble in water (21.7 mg/mL) (1). Pharmaceutical preparations of
caffeine include caffeine anhydrous, caffeine sodium benzoate, and caffeine
citrate.
Figure 13-1 The chemical structure of caffeine. The chemical

structure of caffeine (1,3,7-trimethylxanthine) and adenosine.
Adenosine is an endogenous neuromodulator that has
structural similarities to caffeine. Most of the physiological
effects of caffeine, including the central nervous system
stimulant effects, are likely mediated through adenosine
receptor antagonism.
HISTORY
Caffeine was first isolated from coffee and tea in the early 1800s, and its
chemical structure was identified in 1875. The use of tea, coffee beans, and
cacao pod for psychoactive effects may predate recorded history (2). The
development of worldwide trade in the 17th and 18th centuries propagated
global use of caffeinated foods and beverages (3). In America, the protest of a
British tax on tea became a symbolic focal point for revolution, resulting in the
famous “Boston tea party” in 1773. After the Continental Congress passed a
resolution against tea consumption, coffee became America’s caffeinated drink
of choice (2). Presently, coffee, cocoa, and tea products represent major imports
of the United States. In 2014, the total value of coffee, cocoa, and tea product
imports were 6.3 billion, 4.7 billion, and 615.9 million USD, respectively.
Caffeinated soft drinks (eg, Coca-Cola), introduced at the end of the 19th
century, and caffeinated energy drinks (eg, Red Bull), introduced at the end of
the 20th century, now represent multibillion dollar markets with hundreds of
different brands available to consumers worldwide. Regulation of energy drinks
in the United States has been heretofore quite lax relative to other countries (4),
but increasing incidence of adverse events after consumption of energy drinks
(5) has led to public scrutiny and an ongoing FDA investigation on the safety of
energy drinks and other caffeine-containing foods (eg, caffeine-containing gum,
candy) (6).
EPIDEMIOLOGY
The most current population-based epidemiological data on caffeine use are
derived from two main sources. The National Health and Nutrition Examination
Survey (NHANES) is given annually to a representative sample of children and
adults in the United States and collects information on all foods, beverages, and
supplements consumed in a 24-hour period. The Kantar World Beverage
Consumption Panel included a representative sample of the US population that
completed 7-day Web-based diaries of beverage consumption in 2010-2011.
These surveys consistently find a high rate of regular caffeine use among
children and adults with ~85% of the population age 2 years and older
consuming at least one caffeinated beverage per day. Daily caffeine exposure
rates are estimated to be 43%-63% among 2- to 5-year-olds (7,8), 75% among
older children and adolescents (7), 86%-90% among teenagers and young adults
(9), with rates progressively increasing with age up to 99% of those 65+ years
(8).
More than 95% of all caffeine ingestion comes from beverages. Among
adults, the primary sources of caffeine are coffee and tea, followed by soft
drinks. A review of studies from 1999 to 2011 found increasing use of coffee and
caffeinated energy drinks among children and adolescents, with the frequency of
energy drink use varying considerably across studies (7). Energy drink use has
increased over time with the largest increases among 18- to 24-year-olds (9).
Reliable consumption data for people who use energy drinks habitually are
unavailable, but market data suggest that energy drink use is widespread and
increasing at a rapid pace. From 2008 to 2012, the US energy drink sector grew
60% with annual sales exceeding 10 billion dollars (10). Sales are expected to
double over the next few years.
As acknowledged in these reports, determining precise levels of caffeine
ingestion is limited by difficulties ascertaining the exact amounts of caffeine
contained in beverages. Notwithstanding this limitation, the Kantar Panel
estimated US daily caffeine consumption to be 165 mg for all ages combined,
with the greatest mean intake among consumers ages 35 years and older (ie,
~200-225 mg caffeine per day) (8). A report commissioned by the FDA
concluded that average daily caffeine exposure among adults 22 years and older
was 300 mg (11). In general, coffee drinkers consume 3.3 8-oz cups per day on
average and are exposed to the greatest amounts of caffeine (11,12).
SOURCES OF CAFFEINE
As shown in Table 13-1, sources of caffeine include beverages, foods, dietary
supplements, and over-the-counter and prescription medications. Estimating
caffeine exposure is challenging because of the wide variety of products that
contain caffeine, large differences in serving sizes, variability in caffeine content
across products of the same type, and undisclosed caffeine amounts in some
products. A 12-oz cup of coffee may contain anywhere from 107 to 420 mg of
caffeine. Energy drinks can vary more than 10-fold in caffeine content across
brands. Presently, there is widespread marketing of highly caffeinated dietary
supplements and energy shots (eg, 5-hour ENERGY), and caffeine is added to a
variety of food products (eg, potato chips, jelly beans).
TABLE 13-1 Caffeine Content of Common Foods and

Medications
Caffeine values for name brand items were obtained directly from product labels, the manufacturer’s
website, customer service department, or www.caffeineinformer.com.
Data from Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol. 1996;34:119-129;
McCusker RR, Fuehrlein B, Goldberger BA, et al. Caffeine content of decaffeinated coffee. J Anal Toxicol.
2006;30:611-613; McCusker RR, Goldberger BA, Cone EJ. Caffeine content of specialty coffees. J Anal
Toxicol. 2003;27:520-522.
THERAPEUTIC USES
Caffeine is widely used to aid energy and alertness and prevent sleepiness.
Caffeine is added to a wide range of over-the- counter and prescription
analgesics because of its analgesic-enhancing effects (13). Caffeine
administration can prevent or treat caffeine withdrawal symptoms and
postoperative headache. As a respiratory stimulant, caffeine is used to treat
apnea in neonates and infants (14,15). Because of its lipolytic and thermogenic
effects, caffeine is commonly added to weight loss preparations and nutritional
supplements. Caffeine and other xanthines have been used to treat postprandial
hypotension (16).
NEUROBIOLOGY
Psychostimulant Pharmacological Profile of

Caffeine
Psychostimulants produce psychomotor activation as well as reinforcing and
arousing effects. The “Psychomotor Stimulant Theory of Addiction” implied that
psychomotor activation and reinforcing effects constitute different aspects of the
same underlying mechanism: an increase in central dopamine neurotransmission
(17). This postulate has been supported by a large amount of experimental data.
Particularly significant has been the demonstration that mesencephalic dopamine
cells are especially involved in the processing of a particular kind of salient
stimuli: reward-associated stimuli (18). Apart from increasing responsiveness to
reward-related stimuli, including orienting and approaching responses to those
stimuli (psychomotor activation), dopamine is directly involved in reinforcement
(reinforcing effects). More specifically, dopamine is involved in the learning
(“stamping-in”) of stimulus–reward and reward–response associations that
follow the receipt of reward (19). Classic psychostimulants, such as cocaine- and
amphetamine-like compounds, show strong psychomotor and reinforcing effects,
which are related to their ability to significantly increase the extracellular
concentrations of dopamine in the brain. This is mostly dependent on their
interacting with the dopamine transporter (20). The arousing effects, on the other
hand, suggest an increased responsiveness to all kinds of salient stimuli,
including nonrewarding stimuli. Such arousing effects are largely dopamine-
independent and depend on the activation of several ascending arousal systems,
including noradrenergic and histaminergic systems (21,22).
Caffeine is a psychostimulant with milder psychomotor and reinforcing
effects than classical psychostimulants (21), and it does not directly target
dopaminergic neurotransmission. Caffeine is a nonselective adenosine receptor
antagonist with similar in vitro affinities for A1, A2A, and A2B receptors and with
lower affinity for A3 receptors (23). A1 and A2A receptors are the preferential
targets for caffeine in the CNS because physiological extracellular levels of
adenosine are sufficient to occupy and, therefore, activate A1 and A2A receptors.
On the other hand, adenosine only binds and activates A2B receptors at high
pathological extracellular concentrations (23). A1 receptors are widely expressed
in the CNS, including the spinal cord (23,24), whereas A2A receptors are
particularly concentrated in the striatum (23,25), the main projecting area of the
ascending dopamine system. Striatal adenosine receptors have been associated
with the psychomotor and reinforcing effects of caffeine. On the other hand,
adenosine receptors localized in the brainstem, basal forebrain, and
hypothalamus, in the loci of origin of ascending arousal systems, have been
suggested to be involved in caffeine-induced hyperarousal. Generally, it can be
concluded that striatal A2A and extrastriatal A1 receptors are preferentially
involved in the psychomotor-reinforcing effects and hyperarousal induced by
caffeine, respectively (21,22).
Adenosine A2A-Dopamine D2 Receptor

Heteromers as Main Targets for the
Psychomotor and Reinforcing Effects of
Caffeine
The enigmatic psychomotor activating effects of caffeine provided one of the
main findings that would lead to the field of G protein–coupled receptor
heteromers (26,27). More specifically, it led to the discovery of adenosine–
dopamine receptor heteromers and, even more specifically, to the establishment
of A2A-D2 receptor heteromers as mainly responsible for the psychomotor-
reinforcing effects of caffeine (21,28,29). A2A and D2 receptors are particularly
expressed in the striatum, colocalized in the GABAergic striatopallidal neuron,
where a large amount of experimental evidence indicates there is a predominant
striatal population of both receptors forming functionally and pharmacologically
significant heteromers (28,29). Recent studies suggest that A2A-D2 receptor
heteromers constitute a heterotetrameric structure, with A2A and D2 receptor
homodimers coupled to their cognate Gs/olf and Gi/o proteins, respectively (29).
The heterotetrameric structure allows multiple simultaneous and reciprocal
interactions between adenosine and dopamine and exogenous A2A and D2
receptor ligands (28–30). Simultaneous allosteric interactions between caffeine
and endogenous adenosine and dopamine within the A2A-D2 receptor
heterotetramer determine the ability of caffeine to increase D2 receptor–mediated
signaling in the GABAergic striatopallidal neurons (28–31). Increases or
decreases in the activity of the GABAergic striatopallidal neuron leads to
decreases and increases, respectively, in psychomotor activity. Thus, a
pathogenic hallmark of akinesia in Parkinson disease is a pronounced
hyperactivity of the GABAergic striatopallidal neuron. This is in fact the
rationale for the originally suggested (32) and recently implemented use of A2A
receptor antagonists in this disease (33).
Accumulated knowledge about the function of the A2A-D2 receptor
heteromer therefore indicates that it is a main target for the psychomotor
activating and also reinforcing effects of caffeine (21). However, this is still an
incomplete picture and caffeine also increases dopamine neurotransmission by
additional mechanisms related to blockade of striatal presynaptic A1 receptors
that modulate dopamine release and postsynaptic A1 receptors that form
heteromers with D1 receptors in the GABAergic striatonigral neuron (34). In
addition, recent evidence indicates that A1-D1 receptor interactions also govern
the effect of caffeine at the spinal level, where it potentiates a spinal-generated
locomotor activation (24).
Adenosine A1 Receptors as Main Targets for

the Arousal Effects of Caffeine
Adenosine is a main mediator of sleepiness following prolonged wakefulness,
when it accumulates in the extracellular space of basal forebrain, cortex, and
hypothalamus (22,35). This accumulation leads to A1 receptor–mediated
inhibition of the cells of origin of the corticopetal basal forebrain system; (22,35)
inhibition of corticofugal neurons from the prefrontal cortex that target the origin
of pontine ascending arousal systems, also mediated by A1 receptor (36); and
inhibition of hypothalamic histaminergic and orexinergic ascending arousal
systems, with both A1 and A2A receptors being involved (22,35,36). Several
studies indicate that the A1 receptor is a marker of homeostatic sleep responses
and the need for recovery of lost sleep, which involves rebound sleepiness upon
acute sleep deprivation and cumulative sleepiness upon chronic sleep
deprivation (37,38). In fact, both acute and chronic sleep deprivation lead to an
increase of A1 receptor density in the brain (38–40). Chronic caffeine
consumption also leads to up-regulation of A1 receptors, which therefore seems
to play an important role in the sleepiness, marked fatigue, and drowsiness of
caffeine withdrawal (28,40). Therefore, an important component of the
improvement in attention, performance, and wakefulness by caffeine could be
explained by relieving these A1 receptor–mediated withdrawal symptoms
(28,41). The very prevalent consumption of caffeine may therefore depend
largely on A2A receptor blockade–mediated reinforcing effects and A1 receptor
blockade–mediated and reversal withdrawal-related arousing effects (28).
PHARMACOKINETICS
Absorption and Distribution
Caffeine is rapidly and completely absorbed after oral administration, with peak
levels reached in 30-45 minutes (42). It is readily distributed throughout the
body, with concentrations in blood correlating with those in saliva, breast milk,
amniotic fluid, fetal tissue, semen, and the brain (43). Binding to plasma proteins
is estimated to range between 10% and 35% (44). Saliva caffeine concentrations,
which often exceed 75% of plasma concentrations, are used as a noninvasive
alternative to serum monitoring.
Metabolism
Caffeine metabolism is complex, with more than 25 metabolites identified in
humans (45). Caffeine is metabolized by the cytochrome P-450 liver enzyme
system. In particular the CYP1A2 isoenzyme demethylates caffeine to three
biologically active dimethylxanthines: paraxanthine, theobromine, and
theophylline, accounting for 80%, 10%, and 4% of caffeine metabolism,
respectively (44).
Elimination
On average, caffeine half-life is 4-6 hours, but there are wide individual
differences (44), which are due in large part to CPY1A2 genetic variation (46).
Drugs or conditions that affect the cytochrome P-450 liver enzyme system
significantly alter caffeine elimination. Caffeine’s half-life is prolonged with
liver disease (44), presumably because of lower CYP1A2 activity (47). Caffeine
half-life is markedly increased in infants whose liver enzyme capacity is not
completely developed until about 6 months of age (48). Cigarette smoking,
which induces liver enzymes, decreases caffeine half-life by as much as 50%
(48). Numerous compounds inhibit caffeine metabolism including oral
contraceptives, cimetidine, some quinoline antibiotics (eg, ciprofloxacin),
fluvoxamine, and mexiletine (45,49). Caffeine half-life increases markedly
during the end of pregnancy (50), which could increase the risk of caffeine
toxicity among women who maintain high levels of caffeine use during
pregnancy (51).
PHYSIOLOGICAL EFFECTS
At moderate dietary dose levels, caffeine increases systolic and diastolic blood
pressure (52), constricts blood vessels in the head and neck, increases urine
volume (53), stimulates gastric acid secretions, and is a colonic stimulant (54).
As a diuretic, caffeine also increases detrusor pressure on the bladder of patients
with complaints of urinary urgency and confirmed detrusor instability (55).
Caffeine is a respiratory stimulant (56) and a bronchodilator at high doses (57).
Caffeine increases plasma epinephrine, norepinephrine, renin, and free fatty
acids, particularly in nontolerant individuals (58–60). It also increases
adrenocorticotropic hormone and cortisol (61–63). Caffeine increases insulin
levels in healthy subjects (64) and increases postprandial glucose and insulin
responses among patients with type 2 diabetes who are habitual coffee drinkers
(64,65).
SUBJECTIVE EFFECTS
A single low to moderate doses of caffeine typically produces a profile of
positive subjective effects, including increased well-being, happiness, energy,
arousal, alertness, and sociability, with greater positive mood effects of caffeine
for physically dependent individuals (66). Negative subjective effects of caffeine
are more likely to be observed after acute doses of caffeine >200 mg and include
anxiety, nervousness, jitteriness, negative mood, upset stomach, sleeplessness,
and “bad effects” (66). Individual differences in use, sensitivity, and tolerance
seem to play an important role in the likelihood and severity of negative
subjective effects (67). Individuals with anxiety disorders may be more sensitive
to the anxiogenic effects of caffeine (68), and higher acute doses of caffeine can
also elicit panic attacks (69). The DSM-5 recognizes Caffeine-Induced Anxiety
Disorder, which is defined as anxiety symptoms or an anxiety disorder (eg,
Generalized Anxiety Disorder) caused by caffeine use (70).
PERFORMANCE EFFECTS
Cognitive Performance
Moderate acute doses of caffeine, usually up to 300 mg, tend to increase human
performance on cognitive tasks assessing reaction time, vigilance, as well as
simple and complex attention, with greater effects of caffeine for fatigued
individuals (71). Higher doses of caffeine (eg, >400 mg) may impair
performance in non–sleep-deprived nonusers of caffeine (71). The effects of
caffeine on various memory tasks, higher-order executive functioning, and
decision-making have also been investigated, but results are mixed (71).
Physical Performance
Caffeine is reliably ergogenic across a variety of exercise situations, and in
particular during prolonged exercise, with activity potentially mediated via
multiple mechanisms, including effects on muscle contractility, reduced
perception of effort, and lowered sensations of pain (71).
Withdrawal Reversal
A problem in interpreting the effects of caffeine on performance is that most
studies have compared the effects of caffeine and placebo on the performance of
people who use caffeine habitually who have been required to abstain from
caffeine, usually overnight. Thus, improvements in performance after caffeine
relative to placebo may simply reflect a reversal of withdrawal effects or
restoration to baseline performance (72). However, some studies have shown
caffeine-related performance enhancements among light nondependent caffeine
consumers and nonconsumers (73), nonwithdrawn caffeine consumers (74), as
well as caffeine consumers after a protracted period of abstinence (75). Based on
the preclinical literature, which clearly documents the behavioral stimulant
effects of caffeine, it seems quite likely that caffeine enhances human
performance on some types of tasks (eg, vigilance), especially among
nontolerant individuals. Among high-dose habitual caffeine consumers,
performance enhancements above and beyond withdrawal reversal effects are
perhaps modest at best (72).
REINFORCING EFFECTS
Given that caffeine is the most widely self-administered mood-altering drug in
the world, the circumstantial evidence for caffeine functioning as a reinforcer is
compelling. Several carefully controlled research studies over the past 30 years
provide unequivocal evidence for the reinforcing effects of caffeine (66).
Caffeine reinforcement has been demonstrated with various participant
populations, using a variety of methodological approaches (eg, choice
procedures, ad libitum self-administration), and across different caffeine vehicles
(eg, coffee, soft drinks, capsules). The average incidence of caffeine
reinforcement across studies in people who use caffeine normally is ~40%, with
higher rates observed (ie, 82%-100%) among certain subsamples such as heavy
caffeine consumers, those with histories of substance use disorders, in studies
involving repeated exposure to caffeine and placebo test conditions before
reinforcement testing, and in the context of having to perform a vigilance task
after drug administration (76). Doses as low as 25 mg per cup of coffee and 33
mg per serving of soft drink function as reinforcers (77–79). Doses >50 or 100
mg tend to decrease choice or self-administration, with relatively high doses of
caffeine (eg, 400 or 600 mg) sometimes producing significant caffeine avoidance
(80). Positive subjective effects of caffeine predict the subsequent choice of
caffeine relative to placebo, and negative subjective effects predict the
subsequent choice of placebo relative to caffeine (81). There is good evidence to
suggest avoidance of caffeine withdrawal symptoms increases the reinforcing
effects of caffeine among regular caffeine consumers. For instance, people who
use caffeine who report negative effects of placebo (ie, withdrawal symptoms)
tend to choose caffeine over placebo, and when physical dependence is
manipulated, subjects chose caffeine more than twice as often when they were
physically dependent than when they were not physically dependent (76).
CAFFEINE TOLERANCE
The degree of tolerance development to caffeine depends on the caffeine dose,
the dose frequency, the number of doses, and the individual’s elimination rate
(82). Complete tolerance does not occur at low daily dietary doses. Very high
doses of caffeine (750-1200 mg/d spread throughout the day) administered daily,
produce “complete” tolerance (ie, caffeine effects are no longer different from
baseline or placebo) to some but not all effects (76). Tolerance develops to the
effects of caffeine on subjective drug effect ratings, sleep disruption, diuresis,
parotid gland salivation, increased metabolic rate (oxygen consumption),
increased plasma norepinephrine and epinephrine, and increased plasma renin
activity. Tolerance to caffeine-caused increases in blood pressure occurs but is
incomplete (76).
CAFFEINE INTOXICATION
Caffeine intoxication is a diagnosis in DSM-5 (70) and in the ICD-10 (83).
Caffeine intoxication is defined by the DSM-5 as the emergence of five or more
of the following symptoms after excess ingestion of caffeine: restlessness,
nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal
disturbance, muscle twitching, rambling flow of thought and speech, tachycardia
or cardiac arrhythmia, inexhaustibility, and psychomotor agitation (70). Among
adults, negative effects are not usually observed at acute doses <250 mg, and
caffeine intoxication is typically associated with higher acute doses (eg, >500
mg). Individual differences in sensitivity (eg, metabolic differences) and
tolerance likely influence dose effects.
Caffeine intoxication typically resolves within a day (consistent with
caffeine’s half-life of 4-6 hours) and often with no long-lasting consequences.
However, medical treatment and monitoring are necessary when significant
caffeine overdose occurs. Caffeine can be lethal after ingestion of very high
doses (ie, about 5-10 g), and there is documentation of accidental death and
suicide by caffeine ingestion (84).
It has been suggested that the lack of regulation and availability of highly
caffeinated energy drinks/shots in recent years may be increasing the incidence
of caffeine intoxication, especially among young people. A report by the Drug
Abuse Warning Network found that the number of emergency department visits
involving energy drinks doubled from 2007 to 2011 with most of the 20,783
energy drink–related visits involving males and individuals between the ages of
18 and 25 (5). A report from the national poison data system for 2014 revealed
that the large majority of energy drink cases involved young children and
adolescents (85). Claims that energy drinks have contributed to sudden deaths
have led to public scrutiny and an ongoing FDA investigation on the safety of
energy drinks.
CAFFEINE WITHDRAWAL
The caffeine withdrawal syndrome is well characterized. A 2004 comprehensive
review of carefully controlled caffeine withdrawal research provided a strong
empirical basis for 13 symptoms (Table 13-2). The symptoms were conceptually
grouped into the following five categories and later validated by a factor analysis
(86,87): (a) headache; (b) fatigue or drowsiness; (c) dysphoric mood, depressed
mood, or irritability; (d) difficulty concentrating; and (e) flu-like somatic
symptoms—nausea, vomiting, and muscle pain/stiffness. The caffeine
withdrawal syndrome is defined by the DSM-5 as the presence of at least three
symptoms within 24 hours of abrupt caffeine reduction or cessation. Symptoms
must cause clinically significant distress or impairment in social, occupational,
or other important areas of functioning (eg, unable to care for children, unable to
work). Headache is a hallmark feature of caffeine withdrawal with ~50% of
people who use caffeine regularly reporting headache by the end of the 1st day
of abstinence (86). Caffeine withdrawal headaches have been described as
gradual in development, diffuse, throbbing, and sensitive to movement. Caffeine
abstinence produces rebound cerebral vasodilatation and increased cerebral
blood flow, and such vascular changes are the likely mechanism underlying
caffeine withdrawal headache (88,89).
TABLE 13-2 Empirically Validated Signs and

Symptoms Resulting from Caffeine Abstinence
From Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of
symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). 2004;176:1-
29.
Caffeine withdrawal usually begins 12-24 hours after terminating daily caffeine
intake, although onset as early as 6 hours and as late as 43 hours has been
documented. Peak withdrawal intensity generally occurs 20-51 hours after
abstinence. The duration of withdrawal ranges from 2 to 9 days, with headache
possibly persisting for 3 weeks (87).
Although there is wide variability across individuals, the incidence and
severity of caffeine withdrawal appears to be positively correlated with daily
caffeine dose (90). Nevertheless, caffeine withdrawal has been observed after
repeated dosing as low as 100 mg/d (90,91), and after relatively short-term
exposure to daily caffeine (eg, 3 consecutive days of 300 mg/d), with greater
severity after 7 and 14 consecutive days (90). Low doses of caffeine can
suppress caffeine withdrawal. Among individuals maintained on 300 mg
caffeine/day and tested with a range of lower doses, a substantial reduction in
caffeine dose (to <100 mg/d) was necessary for caffeine withdrawal to manifest
(90).
Individuals who abstain from caffeine during religious holidays and in
preparation for certain medical procedures (eg, blood tests, colonoscopies) and
surgeries may be at risk for caffeine withdrawal. Caffeine withdrawal symptoms
can sometimes be misattributed to other ailments among those who are not
aware of their physical dependence on caffeine.
CAFFEINE USE DISORDER

In general, a DSM-5 substance use disorder diagnosis is considered in the
context of problematic substance use, which may include but not be limited to
features such as withdrawal, difficulty controlling use, use despite harm, using
more than intended, and tolerance. The ICD-10 includes a diagnosis of substance
dependence due to caffeine (92), and Caffeine Use Disorder is now recognized
by the DSM-5 as a condition for further study (70). The DSM-5 research criteria
for Caffeine Use Disorder contain a much more restrictive set of criteria than the
generic DSM-5 substance use disorder criteria that apply to other substances.
That is, an individual must show a problematic pattern of caffeine use leading to
clinically significant impairment or distress, as manifested by all three of the
following criteria occurring within a 12-month period: (a) a persistent desire or
unsuccessful efforts to cut down or control caffeine use, (b) continued caffeine
use despite knowledge of having a persistent or recurrent physical or
psychological problem that is likely to have been caused or exacerbated by
caffeine, and (c) withdrawal, as manifested by either of the following: (i) the
characteristic withdrawal syndrome for caffeine or (ii) caffeine (or a closely
related substance) is taken to relieve or avoid withdrawal symptoms. Other
symptoms that define a substance use disorder by the DSM-5 (such as tolerance,
using more than intended) are also potential features of problematic caffeine use.
However, a more restrictive set of criteria was chosen to prevent overdiagnosis
(93).
A number of studies have identified adults and adolescents with problematic
caffeine consumption based on the generic DSM-IV/TR criteria for substance
dependence or the more recent DSM-5 research criteria for Caffeine Use
Disorder (94,95). Such individuals display a wide range of daily caffeine intake,
are consumers of various types of caffeinated products, are more likely to
experience caffeine reinforcement and severe withdrawal, and are more likely to
have had a history of DSM-defined alcohol abuse or dependence (95). Among a
sample of pregnant women advised to stop caffeine use by their physicians, a
caffeine dependence diagnosis predicted greater caffeine use during pregnancy
and a history of daily cigarette smoking (96).
There have been only a few studies describing treatment for problematic
caffeine use. A recently published clinical trial enrolled 67 individuals seeking
treatment for problematic caffeine use (97). Participants’ baseline daily caffeine
consumption ranged from 200 to 2500+ mg and 84% met criteria for Caffeine
Use Disorder. Treatment consisted of a one-session therapist-guided manualized
intervention for problematic caffeine use including cognitive–behavioral
strategies and 5 weeks of progressively decreased caffeine consumption.
Participants reported a significant reduction in caffeine use by the 6-week
follow-up (ie, a mean reduction from ~600 to 50 mg). In general, caffeine
reduction was maintained at the 1-year follow-up. Additional research is needed
to more fully characterize the features and prevalence of Caffeine Use Disorder,
its clinical significance and prognosis, associated features, and effective
treatment strategies.
GENETICS
Genetic factors account for some of the variability in the use of and effects of
caffeine. Relative to dizygotic twins, monozygotic twins have higher
concordance rates for total caffeine consumption, heavy caffeine consumption,
coffee and tea intake, caffeine intoxication, caffeine withdrawal, caffeine
tolerance, and caffeine-related sleep disturbances with heritability ranging
between 30% and 77% (98). There is evidence that a common genetic factor
(polysubstance use) underlies the use of caffeine, cigarette, and alcohol use, with
28%-41% of the heritable effects of caffeine use (or heavy use) shared with
alcohol and smoking (99). Additional research shows caffeine and nicotine
dependence to be associated with genetic factors unique to these licit drugs (100)
and distinct from illicit drugs (101). Twin studies have also concluded that
caffeine use shares genetic factors with some psychiatric disorders (102).
The CYP1A2 gene, which codes for the primary enzyme responsible for
caffeine metabolism, and the ADORA2A gene, which codes for the adenosine
A2A receptor, are candidate genes that have been most commonly identified as
having associations with caffeine consumption (103,104), effects of caffeine (eg,
sleep, anxiety, vigilance/attention, energy output), and health outcomes,
including risk of hypertension and myocardial infarction (105,106). Recent
large-scale meta-analyses have found genome-wide associations between
caffeine use and various gene loci (including some associated with CYP1A2 and
ADORA2A) warranting further exploration (107).
EFFECTS ON PHYSICAL HEALTH

The relationship between caffeine consumption and physical health has been the
focus of several scholarly books and reviews (48,108–110). Although caffeine is
not associated with any life-threatening illnesses, there are some medical
conditions that may be adversely affected by caffeine or coffee consumption.
Epidemiological research has also provided evidence that caffeine or coffee
consumption may have some protective effects against specific diseases.
Dietary Guidelines
The 2015-2020 Dietary Guidelines of the U.S. Department of Agriculture
suggest that up to 400 mg/d of caffeine from coffee may be part of a healthy diet.
These guidelines do not provide recommendations for caffeine from sources
other than coffee and do not encourage individuals who do not consume caffeine
to start doing so. The Dietary Guidelines are consistent with one scholarly
review of the effects of caffeine on health, which suggested limits of 300 mg/d
for reproductive aged women, 400 mg/d for healthy adults, and 2.5 mg/kg/d for
children (48). For pregnant women, the American College of Obstetricians and
Gynecologists concluded that consuming <200 mg of caffeine per day is unlikely
to cause miscarriage or preterm birth.
Adverse Health Effects

Caffeine can increase blood pressure, influence heart rate variability, and
increase arterial stiffness, but whether such effects represent clinically significant
cardiovascular risk factors is debated (48,111,112). Both caffeinated and
decaffeinated coffees contain lipids that raise total and low-density lipoprotein
cholesterol with higher levels obtained from unfiltered brewing methods (eg,
French press, boiled) (113). Coffee has been shown to exacerbate
gastroesophageal reflux (114); however, it is not clear if it is due to caffeine or
other coffee constituents (115,116). Caffeine is a general risk factor for urinary
incontinence in women (117) and men (118), and reducing caffeine intake has
been shown to decrease urinary incontinence (119). Caffeine consumption
increases urinary calcium excretion and has been linked to bone loss and
fractures, but it has been suggested that the effects of caffeine on calcium loss
may be offset by relatively small intake of milk (120). Although some early case
control studies reported positive associations between caffeine consumption and
certain types of cancer, carefully controlled studies have not provided
convincing evidence that caffeine consumption increases the risk of cancer
development (108,109). There is also no clear association between caffeine use
and peptic or duodenal ulcers (43,121).
Evidence from large-scale prospective studies and meta-analyses suggests
caffeine consumption prepregnancy and during pregnancy may dose-
dependently increase the rate of spontaneous abortion (miscarriage), still birth,
low birth weight, and infants that are small for gestational age (122–124).
Caffeine use is also associated with decreased fecundity, although
methodological differences across studies prohibit definitive conclusions (48).
Caffeine can also have negative effects on planned sleep. Caffeine delays
sleep onset, reduces total sleep time, alters the normal stages of sleep, and
decreases the reported quality of sleep (125–127). Even caffeine taken early in
the day can disrupt nighttime sleep (128). Caffeine-Induced Sleep Disorder is a
diagnosis recognized by DSM-5 characterized by a prominent sleep disturbance
etiologically related to caffeine use (70).
Health Protective Effects

There is an inverse association between coffee, tea, and caffeine consumption
and risk of Parkinson disease (129), and caffeine-derived compounds have been
suggested as potential therapeutic agents for the treatment of Parkinson disease
(130). There is some evidence suggesting protective effects of caffeine
consumption against other forms of dementia and depression, but the data are
more ambiguous (131,132). Systematic review of studies examining the effects
of coffee on liver health outcomes suggest that increased coffee drinking is
associated with reduced progression to cirrhosis for individuals with chronic
liver disease, decreased mortality in individuals with cirrhosis, decreased rate of
liver cancer, improved response to antiviral treatment in individuals with
hepatitis C, and decreased steatohepatitis in individuals with nonalcoholic fatty
liver disease (133). The potential mechanisms of coffee’s hepatoprotective
effects are many, and some are unrelated to caffeine (133). Preclinical research
and systematic review provide evidence that antioxidant coffee constituents
improve glucose metabolism and insulin sensitivity and consequently offer a
protective effect of coffee drinking against type 2 diabetes mellitus, with similar
effects for caffeinated and decaffeinated coffee (120).
Nicotine and Cigarette Smoking

Cigarette smokers consume more caffeine than nonsmokers (134), and twin
studies suggest a high genetic correlation between caffeine use and smoking
(100). Coffee drinking and cigarette smoking tend to temporally covary (135).
Caffeine can increase the reinforcing and stimulant subjective effects of nicotine
(136,137). However, caffeine administration has not been shown to reliably
increase cigarette or nicotine self-administration (138,139), suggesting that the
coffee–smoking interaction is not controlled by the pharmacological effects of
caffeine alone. However, studies have shown that caffeine can increase the
analgesic effects of cigarette smoking (140) and produce moderate decreases in
arousal after cigarette smoking (141). Cigarette smoking abstinence produces
substantial increases in caffeine blood levels among heavy caffeine consumers,
presumably because of the reversal of smoking-induced caffeine metabolism, but
the clinical significance during smoking cessation has not been shown
(134,142,143).
Alcohol
Heavy use and DSM-IV-defined clinical dependence on alcohol is associated
with heavy use and clinical dependence on caffeine (142,144,145). One study
reported substantial increases in caffeine consumption after alcohol
detoxification in patients with alcoholism (146). A study of individuals fulfilling
DSM-IV diagnostic criteria for substance dependence as applied to caffeine
found that almost 60% had a past diagnosis of DSM-defined alcohol abuse or
dependence (147).
Alcohol and Energy Drinks

Despite warnings issued by the U.S. Food and Drug Administration, it is
common, especially among young adults, to mix caffeinated energy drinks with
alcohol. There is growing evidence to suggest that the coingestion of caffeinated
energy drinks and alcohol may be associated with increased harms relative to
alcohol consumed alone. A wealth of cross-sectional data demonstrate that
consumption of alcohol mixed with energy drinks is associated with a range of
problematic behaviors such as increased alcohol consumption and alcohol-
related harms, illicit drug use, sexual risk behavior, and increased drinking and
driving (148). In addition, observational research in bar patrons has found that
consumption of alcohol mixed with energy drinks is associated with higher
breath alcohol concentration or a greater number of alcohol drinks consumed
(149–151). These associations may be explained in part by individual differences
in risk-seeking that precede alcohol and energy drink consumption, but self-
reported motivations for combined energy drink and alcohol use and evidence
from controlled laboratory studies suggest that caffeine decreases the sedative
effects of alcohol and increases stimulant effects, which may reduce perceived
intoxication, prolong drinking, and result in increased alcohol-related harms
(148,152).
Studies have also found that college students who have a higher frequency of
energy drink consumption drink more heavily (153), drive while drunk more
frequently (154), and are at greater risk for DSM-defined alcohol dependence
(155) and illicit drug use (156). More research is needed regarding the risks
associated with energy drink use both alone and in combination with alcohol,
including their possible roles in the development of substance use problems.
Other Drug Interactions

Across animal and human studies, caffeine may potentiate the discriminative
stimulus effects of cocaine (32,157). Caffeine and ephedrine have been shown to
mutually potentiate each other’s discriminative stimulus effects (158). There is
preclinical evidence to suggest that caffeine may increase the toxic effects of
other stimulant drugs such as D-amphetamine, cocaine, and MDMA (159–161).
Both animal and human studies suggest a mutually antagonistic relationship
between caffeine and benzodiazepines (162).
There is some evidence that caffeine inhibits the metabolism of the
antipsychotic clozapine to an extent that might be clinically significant (163).
Because caffeine and theophylline mutually inhibit each other’s metabolism,
caffeine consumption during theophylline therapy should be monitored. Lithium
toxicity may occur after caffeine withdrawal because of decreased renal
clearance of lithium (45).
ACKNOWLEDGMENTS
Preparation of this review was supported, in part, by U.S. Public Health Service
grant R01 DA03890 from the National Institute on Drug Abuse and by
intramural funds of the National Institute on Drug Abuse.
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CHAPTER 14
The Pharmacology of Nicotine and
Tobacco
John A. Dani, Thomas R. Kosten, and Neal L. Benowitz
CHAPTER OUTLINE
Drugs in the Class
Methods of Use
Historical Features
Pharmacokinetics
PharmacologicAL Actions
NeurobiologicAL Mechanisms of Action
Systemic Toxicity
In the United States, 21% of adults used tobacco products regularly in 2014 (1).
Tobacco use is a leading cause of death in the United States, causing more than
480,000 deaths per year (2–5), which is about one in every five deaths (6). The
economic cost of smoking in the United States is more than $300 billion a year,
including nearly $170 billion in direct medical costs and $156 billion in lost
productivity (5). Worldwide, tobacco causes nearly 6 million deaths per year,
and that number is on the rise (5,7,8).
Tobacco smoke contains more than 7000 chemicals, including over 70
known carcinogens (9). While multiple constituents may contribute to the
reinforcing properties of tobacco (10,11), nicotine is the main addictive
component. Therefore, understanding the pharmacology of nicotine is important
in devising effective treatments.
DRUGS IN THE CLASS

Nicotine is a naturally occurring alkaloid that serves as an insecticide in many
plants. Nicotine is a tertiary amine that consists of a pyridine and a pyrrolidine
ring. There are two stereoisomers of nicotine. The (S)-nicotine form (Fig. 14-1)
found in tobacco is the active isomer that binds to diverse nicotinic acetylcholine
receptor (nAChR) subtypes throughout the central nervous system (CNS). The
(R)-nicotine form is a weak agonist at cholinergic receptors. During smoking,
some racemization takes place, and small quantities of (R)-nicotine are found in
cigarette smoke. In addition, because nicotine is a tertiary amine, it can exist in a
charged and uncharged form. In the charged form, nicotine cannot cross
membranes unaided, and it binds to nAChRs (12,13). In the uncharged form,
nicotine is membrane permeable. Therefore, nicotine can influence intracellular
processes indirectly via nAChRs and directly by entering into the cytoplasm
(14,15).
Figure 14-1 The chemical structure of nicotine. The chemical

IUPAC name is 3-(1-methylpyrrolidin-2-yl)pyridine and the
chemical formula is C10H14N2.
In humans, nicotine is a psychostimulant and mood modulator (2,4). Like other

psychostimulants, nicotine may temporarily improve alertness and relieve
withdrawal. After becoming addicted, smokers report arousal, relaxation, and
relief from stress and hunger after smoking. Thus, nicotine becomes a mood
leveler, causing arousal during fatigue and relaxation during anxiety (2,4). Many
of these observed effects may result from relief of nicotine withdrawal, which
occurs commonly throughout the day.
METHODS OF USE
Mainly nicotine and the reinforcing sensory stimulation associated with tobacco
use are responsible for the compulsive use of tobacco in the form of cigarettes,
bidis, cigars, pipes, water pipes, snuff, and chewing tobacco (2,4,6,7,13,16).
Nicotine replacement medications that are used to stabilize the nicotine
withdrawal syndrome include nicotine polacrilex gum, transdermal patches,
nasal spray, inhalers, buccal lozenges, and oral nicotine solutions. These forms
of replacement therapy have comparable efficacy, but the patch has the highest
compliance. Recently, electronic cigarettes (e-cigarettes or electronic nicotine
delivery systems [ENDS]) have become widely available. These devices look
like cigarettes but are made of plastic and metal and usually heat a nicotine
solution to generate a nicotine-containing aerosol that is inhaled. In contrast to
regular cigarettes, ENDS aerosol is generated without full combustion of plant
material. ENDS have been marketed for use when one cannot smoke regular
cigarettes and/or to cut down or quit combusted cigarette use; however, their
clinical effectiveness remains uncertain (17). While the devices may reduce toxic
compounds, they may also introduce other new toxicants while still maintaining
exposure to inhaled nicotine, which may have its own long-term harms.
Nicotinic AChRs are involved in critical brain maturation processes, and there is
some concern that nicotine exposure from ENDS may induce epigenetic changes
that sensitize the brain to other drugs and prime it for future substance use (18).
As well, nicotine has long been implicated as a risk factor for cardiovascular
disease and may promote tumor development, but it is not a tumor initiator in
carcinogenesis (19). Thus, substituting tobacco cigarettes with ENDS may
substantially reduce exposure to selected tobacco-specific toxicants, but ENDS
overall safety is still controversial (7,20). Furthermore, their effectiveness as a
treatment has been variable. Like most addictive drugs, the method of
administration modifies the addictive influence. Nicotine is much more addictive
during rapid administration, as obtained by aerosolized (vapers) or smoking
tobacco, than during the slow administration associated with a patch.
HISTORICAL FEATURES
Native American tribes cultivated and used tobacco for many different purposes
for thousands of years before the arrival of Europeans (21). Tobacco was first
commercially grown for the European market at the first permanent English
settlement in America, Jamestown, which was founded in 1607. Tobacco became
an important economic influence in the British American colonies and the early
United States (21,22). The World Health Organization estimates that one-third of
the global adult population smokes, and because tobacco use is on the rise in
developing countries, it is one of the few causes of death that is increasing (3,6).
PHARMACOKINETICS
Absorption, Distribution, Metabolism, and

Elimination
The absorption of nicotine depends on its pH. Below pH 6, smoke contains <1%
unprotonated (free or free base) nicotine. As the pH rises, so does the proportion
of unprotonated nicotine. At pH 7.26, 15% of the nicotine is unprotonated,
increasing to 50% at pH 8. Unprotonated nicotine is present mainly in the
aerosol phase of the smoke, whereas protonated nicotine is contained primarily
within particles in the smoke aerosol (23). Unprotonated nicotine is readily
absorbed through the mucous membranes of the oral and nasal cavities (24).
Tobacco products such as cigars, many pipe tobaccos, snuffs, and chewing
tobaccos present nicotine either as an unionized (unprotonated), aerosolized
component of smoke or as an alkaline solution of nicotine. Tobacco smoke with
pH levels above 6.2 contains increasing amounts of free ammonia, nitrates that
are partially reduced to ammonia during smoking, and other volatile basic
components.
Because alkaline smoke is irritating to the pharynx, it is harsh and difficult to
inhale. Therefore, smoke from most cigarettes has an acidic pH. The ionized
nicotine in such smoke is largely dissolved in the aerosol droplets. After small
droplets of tar and nicotine are inhaled and deposited in small airways and
alveoli, the protonated nicotine is buffered to a physiological pH and absorbed.
Inhaled nicotine avoids first-pass hepatic metabolism. It is quickly delivered
from the large surface area of the alveoli and circulation in the lung to the
arterial bloodstream and then to the brain and other tissues.
Nicotine reaches the brain approximately 20 seconds after inhalation, and it
rapidly occupies nAChRs (occupying one-third of the brain’s nAChRs after 1
puff and 88% after 1 cigarette). This rapid and near-total occupancy of the
human brain’s high-affinity α4β2-containing nAChRs lasts >3 hours (25).
Although levels of nicotine bound to nAChRs in the brain continue to rise
slowly and are maintained for hours, the initial relatively rapid rate of rise of
nicotine at brain targets, which meaningfully occurs in minutes, is likely to be
the determinant for nicotine’s immediate impact on the CNS. The delivery of
nicotine from moist snuff (eg, Copenhagen) is slower, with the plasma
concentration of nicotine continuing to rise throughout a 30-minute period of use
(26). Interestingly, the subjective nicotine craving is relieved in relation to the
nicotine dose and time course (26).
The relatively rapid delivery of nicotine to the brain in the smoking process
allows precise dose titration so that the smoker can obtain the desired effects.
Smokers can control nicotine intake by altering their puff volume, the number of
puffs they take from a cigarette, the intensity of puffing, and the depth to which
they inhale. Smokers also can increase smoke intake by blocking the ventilation
holes of the filter with their fingers or their lips. Because of the complexity of
smoking, the dose of nicotine cannot be accurately predicted from the nicotine
content of the tobacco or a cigarette’s machine-rated yield (27). Individuals
smoke to obtain desired levels of nicotine from cigarettes in ways that largely
compensate for the engineering features that reduce the amount of nicotine
deposited on a filter pad in standard smoking machine tests.
Nicotine is poorly absorbed from the stomach because of the acidity of the
gastric fluid, but it is well absorbed in the small intestine, which has an alkaline
pH as well as a large surface area. When nicotine is administered in capsules,
peak concentrations are reached in just over an hour. Nicotine undergoes first-
pass metabolism; its oral bioavailability is approximately 45% (28).
Nicotine obtained from tobacco reaches high initial concentrations in the
arterial blood and lungs. After nicotine is absorbed into the bloodstream, it has a
volume of distribution of about 180 L, with <5% binding to plasma proteins.
Subsequently, nicotine distributes into the brain, storage adipose, and muscle
tissue. Arterial blood levels of nicotine are two- to sixfold higher than venous
blood levels (28,29). The average steady-state concentration of nicotine in the
body tissues is 2.6 times the average steady-state concentration of nicotine in the
blood (28). Nicotine crosses the placenta freely and has been found in the
amniotic fluid and in the umbilical cord blood of neonates. Nicotine also is
found in breast milk at concentrations approximately twice those found in blood.
Based on a half-life of 2 hours or more, nicotine accumulates during a day of
regular smoking (3-4 half-lives) and persists for 6-8 hours after smoking ceases.
Steady-state plasma nicotine levels, which plateau in the early afternoon,
typically range between 10 and 50 ng/mL. The increment in blood nicotine
concentration after smoking a single cigarette ranges from 5 to 30 ng/mL,
depending on how the cigarette is smoked (24,28). Peak blood concentrations of
nicotine are similar for cigar smokers, users of snuff, chewers of tobacco, and
those who smoke cigarettes. The rate of rise of nicotine concentrations is slower
with use of snuff and chewing tobacco, with peak nicotine levels occurring at
20-30 minutes. Individual smokers seem to manipulate their nicotine intake to
maintain a consistent level of nicotine from day to day (27). Based on positron
emission tomography imaging, the distribution of nicotine onto nAChRs is
slower than the rise in the bloodstream (25).
Smoking represents a multiple-dosing situation throughout the day, with
considerable accumulation of nicotine in the body tissues (including the brain).
Nicotine persists in the body around the clock. Peaks and troughs in blood
nicotine concentrations follow each cigarette (Fig. 14-2), but those variations are
smoothed out within the brain. As the day progresses for the regular smoker, the
overall level of nicotine rises, and the potential influence of each dose becomes
less important. Tolerance occurs, so that the effects of individual cigarettes tend
to lessen throughout the day. Overnight abstinence results in low nicotine levels
and considerable resensitization of nicotinic receptors to nondesensitized states
(Fig. 14-2). The populations of nAChR subtypes begin to change as other
molecular mechanisms involving neuroadaptations come into play after days and
weeks of tobacco use (2,13,30).
Figure 14-2 A simulation of the plasma nicotine

concentration throughout the day in relation to continued
cigarette smoking until later in the evening.
Nicotine is extensively metabolized primarily in the liver and to a lesser extent

in the lung and in the brain (28). On average, 80% of nicotine is metabolized to
cotinine, with smaller fractions metabolized to nicotine N-oxide and nicotine
glucuronide. Cotinine is further metabolized to trans-3′-hydroxycotinine, the
major nicotine metabolite found in the urine, as well as cotinine glucuronide,
cotinine methonium ion, 5′-hydroxycotinine, and cotinine-N-oxide and trans 3’-
hydroxycotinine glucuronide. About 17% of cotinine is excreted unchanged in
the urine (28). CYP2A6 is primarily responsible both for the C-oxidation of
nicotine to cotinine and for the oxidation of cotinine to trans-3′-hydroxycotinine.
The ratio of trans-3′-hydroxycotinine to cotinine, which can be measured in
blood, saliva, or urine of tobacco users, is a relatively stable biomarker of
CYP2A6 activity and the rate of metabolism of nicotine (31). The rate of
nicotine metabolism is a determinant of the level of nicotine addiction and
response to nicotine/tobacco use disorder treatments (7,32). Renal clearance
accounts for 2%-35% (averaging 10%) of total nicotine clearance depending on
the urine pH.
Sex and race influence nicotine metabolism (33). Women metabolize
nicotine faster than men, and women who take estrogen-containing oral
contraceptives metabolize nicotine faster than women who do not (34). The
metabolism of nicotine during pregnancy is even faster, consistent with a dose
effect of estrogen on CYP2A6 activity (35). African Americans obtain on
average 30% more nicotine per cigarette, and they clear nicotine and cotinine
more slowly than do Caucasians (36). The slower nicotine clearance is due to the
less rapid oxidative metabolism of nicotine to cotinine, related at least in part to
a higher prevalence of CYP2A6 gene variants associated with reduced activity in
African Americans (37,38). African Americans also exhibit population
polymorphism in the rate of nicotine N-glucuronidation, with a subpopulation of
slow metabolizers, due to UGT2B10 gene variants, not found in Caucasians
(38,39). Black men also have a higher incidence of mortality from lung cancer
than do White men, particularly at lower levels of cigarette consumption (37).
Chinese Americans have both a lower nicotine intake per cigarette and smoke
fewer cigarettes per day than do Caucasians (39). Chinese Americans also
metabolize nicotine and cotinine more slowly than do Caucasians or Hispanic
Americans. Slower metabolism in Chinese Americans is consistent with the
higher prevalence of CYP2A6 alleles associated with slow metabolism among
Asians (40). Because nicotine intake per cigarette is a marker for tobacco smoke
exposure per cigarette, these findings suggest why Chinese American smokers
have lower rates of lung cancer than either African Americans or Caucasians
(37). Ethnic variations in nicotine intake per cigarette, the number of cigarettes
smoked, and the metabolism of nicotine may form the basis for population-based
differences in the incidence and prevalence of progression from nicotine use to
addiction, as well as the associated risk of tobacco-related disease.
Smoking and metabolism are also affected by the CYP2A6 gene, which
codes for the primary enzyme responsible for the oxidation of nicotine and
cotinine. The rate of nicotine metabolism varies widely among different
smokers, however, even among those with similar CYP2A6 genotype
(24,33,41). Rapid metabolizers smoke more cigarettes per day than slower
metabolizers, presumably to maintain desired levels of nicotine. Studies using
the ratio of the nicotine metabolites trans-3′-hydroxycotinine/cotinine (known as
the nicotine metabolite ratio or NMR) have shown that slow metabolizers are
more likely to quit smoking when treated with placebo or nicotine patches (42).
The mechanism of this effect is not definitely known, but may be that fast
metabolizers eliminate nicotine faster from the blood and so have more severe
withdrawal symptoms between cigarettes, making smoking more of a negative
reinforcer. In addition, more rapid elimination of nicotine from the brain in faster
metabolizers could reduce the extent of tolerance such that the next cigarette is
more rewarding, making smoking more of a positive reinforcer. The rate of
nicotine metabolism is being evaluated as a way to personalize tobacco use
disorder treatment. A recent prospective clinical trial demonstrated that slow
metabolizers undergoing treatment had similar quit rates when treated with
nicotine patch or varenicline, while normal metabolizers had much higher quit
rates with varenicline compared to nicotine patch (43).
Biochemical Assessment of Exposure to

Nicotine and Tobacco
Blood, salivary, and plasma cotinine are most commonly used as biochemical
markers of nicotine intake. Other measures of smoking include expired breath
carbon monoxide concentrations, blood carboxyhemoglobin concentrations, and
plasma or salivary thiocyanate concentrations and urine 4-
(methylnitrosamino)-1-(3) pyridyl-1-butanol (NNAL). NNAL is a metabolite of
the tobacco-specific nitrosamine and lung carcinogen 4-(methylnitrosamino)-1-
(3)pyridyl-1-butanone (NNK) (44,45). Measurement of the minor tobacco
alkaloids anabasine and anatabine as well as NNAL in urine can be used as a
biomarker of tobacco use in individuals who are using nicotine medications (46).
The 16-hour half-life of cotinine makes it useful as a plasma and salivary
marker of nicotine intake. Salivary cotinine concentrations correlate well with
blood cotinine concentrations (r = 0.82-0.90) (47). The cotinine level produced
by a single cigarette is 8-10 ng/mL. It takes several hours for the cotinine to peak
after a cigarette is smoked. A cotinine value >14 ng/mL typically indicates
smoking (48). A smoker with a plasma cotinine concentration of 100 ng/mL
would have an estimated intake of 8 mg nicotine per day, which corresponds to
smoking approximately a half pack of cigarettes per day (49). Cotinine blood
levels average about 250-300 ng/mL in regular smokers but range from 10 to
900 ng/mL. Because of individual variability in the fractional conversion of
nicotine to cotinine and in the rate of elimination of cotinine itself, blood levels
of cotinine are not perfect quantitative markers of nicotine intake in individual
smokers but are useful in studying populations of smokers. Cotinine levels may
persist for up to 7 days after cessation of regular smoking. The gold standard for
estimating daily nicotine intake from tobacco use is the sum of nicotine and its
metabolites in urine (44).
Breath measurements of expired air that contain more than 10 parts/million
of carbon monoxide (CO) usually indicate tobacco smoking within the past 8-12
hours (48). Elevated CO levels in the absence of smoking may be the result of
exposure to environmental pollutants, such as faulty gas boilers, car exhausts,
and smog. Persons who are lactose intolerant exhale hydrogen after ingesting
milk. Several monitors misinterpret this exhaled hydrogen as CO (50).
Hydrogen cyanide is inhaled as a combustion product of nitrogen-containing
compounds. It is metabolized in the body from thiosulfate to thiocyanate, which
can be detected in the blood and saliva (51). Thiocyanate levels also may be
affected by consumption of common foods (such as almonds, tapioca, cabbage,
broccoli, and cauliflower). In addition, hydrogen cyanide is produced when
burning other plant materials, in building fires, and car exhaust fumes. Assays of
thiocyanate are insensitive to low amounts of smoking, and thiocyanate levels
can remain elevated for weeks after smoking has ceased. CO and cotinine levels
generally are preferred to thiocyanate levels in the assessment of smoking.
Unique to tobacco is the nicotine-derived nitrosamine NNK, which is
metabolized in the body to NNAL, which in turn is excreted in urine (52). The
half-life of NNAL is much longer than cotinine (10-16 days) and is a better
biomarker of long-term or intermittent exposure (52).
Drug Interactions With Tobacco and Nicotine

Smoking accelerates the metabolism of many drugs, particularly those
metabolized by CYP1A2 (53). Although other smoke components may play a
role, polycyclic aromatic hydrocarbons are believed to account for the enzyme-
inducing effects of smoking. Nicotine does not induce most enzymes but may
increase CYP2E1 and inhibit CYP2A6 enzymatic activity. Cigarette smoking
induces the metabolism of theophylline, propranolol, flecainide, tacrine,
caffeine, olanzapine, clozapine, imipramine, haloperidol, pentazocine, estradiol,
and other drugs. When smokers stop smoking, as often occurs during
hospitalization for an acute illness, the doses of these medications may need to
be lowered to avoid toxicity. Thus, stopping smoking affords patients an added
benefit of potentially needing lower doses of therapeutic medications and having
fewer medication-related side effects.
Several pharmacodynamic interactions arise between cigarette smoking and
other drugs. Cigarette smoking results in faster clearance of heparin, possibly
because of smoking-related activation of thrombosis, with enhanced heparin
binding to antithrombin III. Cigarette smoking and oral contraceptives interact
synergistically to increase the risk of stroke and premature myocardial infarction
in women. Cigarettes appear to enhance the procoagulant effect of estrogens. For
this reason, oral contraceptives are relatively contraindicated in women who
smoke cigarettes. The stimulant actions of nicotine inhibit reductions in blood
pressure and heart rate from beta-adrenergic blockers. Smoking results in less
sedation from benzodiazepines and less analgesia from some opioids. Smoking
also impairs the therapeutic effects of histamine H2-receptor antagonists used in
treating peptic ulcers. Cutaneous vasoconstriction by nicotine can slow the rate
of absorption of subcutaneously administered insulin.
PHARMACOLOGICAL ACTIONS
Nicotine has a complex dose–response relationship (54,55). At low doses (such
as those achieved by smoking a cigarette), nicotine acts on the sympathetic
nervous system to acutely increase blood pressure, heart rate, and cardiac output
and to cause cutaneous vasoconstriction. At higher doses, nicotine produces
ganglionic stimulation and the release of adrenal catecholamines. At extremely
high doses, nicotine causes hypotension and slowing of the heart rate, possibly
via peripheral ganglionic blockade or vagal afferent nerve stimulation. Although
blood pressure throughout the day while smoking is higher than when that
person is not smoking, chronic nicotine exposure in and of itself does not cause
hypertension because of the development of tolerance to nicotine’s
cardiovascular effects (56). Nicotine also causes muscle relaxation by
stimulating discharge of the Renshaw cells or pulmonary afferent nerves while
inhibiting the activity of motor neurons. Importantly, nAChRs are centrally
involved in learning and memory functions within the human brain (12). As
such, nicotine addiction is increasingly being understood as a learning disorder
of adolescence, in relation to the effect of nicotine on the adolescent brain.
Secondhand smoke exposure to the developing brain has been associated with
attention deficit hyperactivity disorder (ADHD) (57).
Psychoactive Effects
The primary CNS effects of nicotine in smokers are arousal, relaxation
(particularly in stressful situations), and enhancement of mood, attention, and
reaction time, with improvement in performance of some behavioral tasks. Some
of this improvement results from the relief of withdrawal symptoms in addicted
smokers, rather than as a direct enhancing effect (58–60). It is important for
patients and clinicians to realize that nicotine/smoking more often reverses some
effects of abstinence, rather than directly relieving stress and improving
cognition. In a comparison of self-rated feelings of stress, arousal, pleasure, and
evaluations of cognitive function in 25 cigarette smokers, 25 temporarily
abstaining smokers, and 25 nonsmokers, the abstaining smokers reported
significantly worse psychological states on every assessment measure than did
the nonsmokers and smokers, who did not differ from each other (61). Thus,
smokers may need regular doses of nicotine to feel normal rather than to
enhance their capabilities.
The psychoactive effects of nicotine and tobacco are determined not only by
the route and speed of drug administration and the pharmacokinetic parameters
that determine the concentration at receptor sites over time but also by a variety
of host and environmental factors. The magnitude of nicotine’s subjective effects
may depend on the predrug subjective state, level of activity, genetic
predisposition, history or current intake of other drugs, expectancy of the
individual, and other situational factors (16,62–66). Nicotine’s effects are
dependent on the initial conditions (67). For example, low-activity rats become
more active on exposure to nicotine, whereas the reverse occurs in high-activity
rats. Similarly, nicotine has stimulant-like effects on human
electroencephalograms during quiet conditions but minimal effects during high-
noise conditions (68).
In regular smokers, nicotine’s ability to cause stimulation when smoked at a
low level of arousal (such as fatigue) and to affect relaxation when smoked at a
high level of arousal (such as anxiety) underlies its reinforcing effects under a
range of conditions (67). Smokers increase their smoking under both low- and
high-arousal conditions (69). People who use nicotine like to fine-tune their
disposition at a given time and may think subtle stimulation or relaxation effects
from smoking are beneficial. However, many of these effects are more a result of
relief of withdrawal symptoms (negative reinforcement) as opposed to gains in
brain function above that of a nonsmoker. The subtle modulatory effects
preferred by tobacco users are in contrast to the flagrant intoxicating effects
desired by some users of alcohol and other psychoactive substances.
Gender differences appear to affect nicotine responsiveness. Women have
less sensitivity to changes in nicotine dose during nicotine discrimination
experiments, and they may not benefit as much as men from nicotine
replacement therapy during tobacco use disorder treatment (70). Women may be
influenced more by non-nicotine stimuli, such as the olfactory and taste
attributes of cigarette smoke, indicating greater conditioned reinforcement (71).
Genetic Predisposition
Genetics mediate differences in the development of nicotine or tobacco use
disorder (72). Different mice strains react differently to nicotine, self-administer
nicotine to different extents, differ in the ability to develop tolerance, and have
different numbers of nicotine receptor binding sites (73). In humans,
monozygotic twins are more similar than dizygotic twins with respect to
smoking behavior, and the heritability of DSM-defined nicotine dependence is
0.59 in male smokers and 0.46 in female smokers (74). Twin studies also
demonstrate a genetic influence on nicotine withdrawal symptoms (60).
Family linkage studies and candidate gene association studies suggest a
number of loci or particular genes that are associated with smoking behavior, but
the smoking phenotypes vary considerably from study to study (64). Although
candidate genes coding for various receptors and neurotransmitter systems have
been suggested, genome-wide association studies have most compellingly
identified single nucleotide polymorphisms in the genes encoding nicotinic
acetylcholine receptor subunits (65,66,75–77). The CHRNA5–CHRNA3–
CHRNB4 nAChR subunit cluster on chromosome 15q25 is associated with the
number of cigarettes smoked per day and serum cotinine levels, as well as with
risk for lung cancer, peripheral arterial disease, and chronic lung disease (64,65).
SNP rs16969968 in CHRNA5, leading to an amino acid change in the α5
nAChR subunit protein, produced a slight loss of function of the α5-containing
nAChRs and was compellingly linked to increased cigarette usage (76,78). Also,
the CHRNB3–CHRNA6 gene cluster on chromosome 8 was implicated from
both genome-wide association studies and candidate gene-based association
studies (66). Two distinct loci within this region were implicated: one upstream
of the CHRNB3 gene and the other, rs4952, a coding SNP in that gene.
Functional studies by genetic manipulation in animal models also have indicated
the importance of the nAChR α6 subunit, which is highly expressed with the
midbrain dopamine (DA) system where it influences nicotine self-administration
(13).
The other gene that clearly affects smoking behavior and cancer risk is the
CYP2A6 gene, which codes for the primary enzyme responsible for the
oxidation of nicotine and cotinine (64). CYP2A6 affects cigarette smoking
behavior and cancer risk. This gene is polymorphic, and reduced function
variants of the gene are associated with smoking fewer cigarettes per day and a
lower risk of lung cancer (79,80). Other genome-wide association studies point
to several other genes as potential genetic determinants of DSM-defined nicotine
dependence, including neurexin 1, VPS13A (vacuolar sorting protein), KCNJ6 (a
potassium channel), and the GABA A4 receptor genes (75,77). Some of these
genes, such as the neurexin 1 gene, are related to cell communication. Other
genome-wide association studies have identified a number of genes affecting cell
adhesion and extracellular matrix molecules that are common among various
addictions, consistent with the idea that neural plasticity and learning are key
determinants of individual differences in vulnerability to drug addiction (81).
Psychiatric Comorbidity
Tobacco use is most highly prevalent and more intense among psychiatric
patients and among those who use other drugs (2). Among those with mental
illness, 36% are current smokers, compared to 20% among adults with no mental
illness (82). Individuals with schizophrenia, depression, and ADHD have a
higher prevalence of cigarette smoking than the population as a whole. These
groups of patients have more difficulty in quitting compared with smokers
without mental illness, often experiencing greater depression after stopping
smoking.
Among those with schizophrenia, 70%-88% are smokers (83). People with
schizophrenia have diminished sensory gating to repeated stimuli, an
abnormality reversed for tens of minutes by nicotine and clozapine, but not
haloperidol (84). Nicotine also reverses some haloperidol dose–related
impairments on a variety of cognitive tasks and relieves some of the negative
symptoms (such as blunted affect, emotional withdrawal, and lack of spontaneity
and flow of conversation) that occur with schizophrenia. Genetic linkage in
families with schizophrenia supports a role for the nAChR α7 subunit, with
potential linkage at the α7 locus on chromosome 15 (85). These data suggest
there may be a shared underlying neurobiology for both nicotine/tobacco use and
schizophrenia. People who smoke experience fewer side effects from
antipsychotic drugs, presumably from the stimulating effects of nicotine, which
also may contribute to a higher prevalence of smoking among people with
schizophrenia.
Rates of DSM-defined nicotine dependence are substantially higher among
adults with ADHD (40%) than in the general population (about 20%) (86).
Among adults who smoke, the presence of ADHD is associated with early
initiation of regular cigarette smoking, even after controlling for confounding
variables such as socioeconomic status, IQ, and psychiatric comorbidity.
Nicotine administered through transdermal patches improves the attentional
symptoms of ADHD (87).
Population-based epidemiological studies (88) found a lifetime prevalence of
depression of 59% among subjects who had ever smoked, compared with 17% in
the general population. Other reports confirm that the prevalence of smoking in
individuals with major depression is twice that observed in the general
population (89). A history of major depression may speed the progression from
nicotine use to tobacco use disorder. Twin studies support a model with common
risk factors for both depression and cigarette smoking (90).
Depression sensitizes people who smoke to the influence of stress (2,91),
making the individual more susceptible to drug reward. Depression and anxiety
often accompany nicotine withdrawal, particularly for abstinent smokers with
psychiatric illness. Relief from specific aspects of those symptoms motivates
relapse. Thus, people who smoke become conditioned to expect nicotine to
provide partial relief from stress and depression, as it does from the symptoms of
withdrawal (91). Smokers with a history of depression who stop smoking are at
risk of developing more severe withdrawal symptoms, have poorer outcomes,
and are more likely to experience a depressive episode, especially during the
first 3 months after stopping smoking (2,91).
Discrimination and Self-administration

Squirrel monkeys and rodents are able to distinguish the subjective effects of
nicotine and nicotine analogues from drugs of other classes. This effect is
attenuated by pretreatment with mecamylamine, a centrally acting nicotinic
receptor antagonist, but not with hexamethonium, a peripheral antagonist that
does not enter the brain. Animals will self-administer nicotine, but the
environment, dose, and timing of the reinforcement schedule are more critical
with nicotine than with, for example, cocaine. Likewise, human volunteers will
self-administer intravenous nicotine (88). They describe the experience as
pleasurable and similar to that evoked by cocaine. Human smokers also regulate
the nicotine levels that they self-administer (27). Smokers pretreated with
mecamylamine smoke more to overcome the blocking effects of this antagonist
(59).
Human smokers get “secondary reinforcement” from the irritant effects of
nicotine on the tissues of the mouth and throat. Experienced smokers can use the
tissue-irritant effects to assess how much nicotine they are receiving when
smoking (16). A short-term reduction in cigarette craving is seen when the
sensory input from tobacco smoke is simulated with ascorbic acid or black
pepper extract. Products that replicate the taste, flavor, throat, and chest
sensations of cigarette smoking or the sensorimotor handling of a cigarette may
reduce craving and some of the symptoms of nicotine withdrawal. Some of these
products are being developed as treatments for tobacco use disorder.
Addiction
The average age of first smoking is 15 years old. Nicotine obtained through
chewing tobacco and cigarettes often precedes the use of other drugs (92,93).
The earlier the age at which use begins, the more difficult it is for the person
with addiction to quit. Many persons have been exposed to nicotine in utero as a
result of smoking by their mothers (94). Nicotine exposure alters nicotinic
receptor numbers and influences their function. In smokers who progress to
chronic use, tolerance develops rapidly to the headache, dizziness, nausea, and
dysphoria associated with the first cigarette. However, tolerance is incomplete;
the intake of as little as 50% more than the usual dose can result in symptoms of
toxicity. Chronic use is associated with the regular intake of quantities far larger
than those used initially, even though consumption levels typically remain steady
for many years after addiction has been established.
Conditioned cues (drug-associated memories) become established during the
fine-tuned dosing of nicotine (55,95). Chronic nicotine exposure increases
nAChR numbers significantly, including in areas critical to storage and retrieval
of memories (96). As a result of conditioning and the direct effects of nicotine on
these brain areas, desiring a cigarette becomes associated with everyday events
such as driving a car, finishing a meal, talking on the telephone, waking from
sleep, and taking a break. Tobacco users link the need to modulate their moods
with smoking. The imagery promoted by cigarette advertising adds to this
expectation. Thus, a person who begins smoking a pack of cigarettes per day at
age 17 would experience thousands of finely tuned doses of nicotine-conditioned
internal emotional states and external cues by their mid-20s. The quantity and
power of this conditioning are unique to cigarette smoking, and it is a reason that
smokers find cigarette smoking so difficult to quit.
The regular use of tobacco commonly leads to its compulsive use (55). There
have been attempts to correlate the severity of nicotine addiction with factors
such as the duration of smoking, potency of cigarettes, puff frequency, puff
duration, and inhalation volume. However, these variables only weakly correlate
with biochemical measures, and they do not predict the intensity and extent of
withdrawal symptoms. The Fagerstrom Test for Nicotine Dependence is one of
the most widely accepted measures of the severity of nicotine physical
dependence (97). Many studies show a relationship between the Fagerstrom Test
for Nicotine Dependence and the ability to achieve abstinence from tobacco. The
two items in the Fagerstrom test that convey the most predictive information are
number of cigarettes smoked per day and time from waking to first cigarette of
the day. These two items have been combined into the heaviness of smoking
index (97).
There is a high rate of relapse among individuals who try to quit smoking
(2,7). Population surveys consistently find that up to 75% of adults who smoke
want to stop. About one-third actually try to stop each year, but <3% succeed
unaided (98). Among persons who experience myocardial infarctions,
laryngectomies, chronic obstructive pulmonary disease, and other medical
sequelae of smoking, more than 50% revert to cigarette use within days or weeks
after leaving the hospital.
Withdrawal
Tobacco use is sustained, in part, by the need to prevent the symptoms of
nicotine withdrawal, that is, negative reinforcement (13,58,59,99). The
symptoms of withdrawal vary in severity from person to person, but those
symptoms include craving for nicotine, irritability and frustration or anger,
anxiety, depression, difficulty concentrating, restlessness, and increased appetite.
Performance measures such as reaction time and attention are impaired during
withdrawal. Although these symptoms often are distressing and can be
disruptive to interpersonal functioning, they are not in themselves life
threatening. Most acute withdrawal symptoms reach maximum intensity 24-48
hours after cessation and then gradually diminish over a few weeks (58,100).
Some (including dysphoria, mild depression, and anhedonia) may persist for
months. The extinction of tobacco-associated conditioned cues requires months
to years. That nicotine itself is responsible for the withdrawal symptoms is
supported by the appearance of similar symptoms with sudden withdrawal from
the use of chewing tobacco, snuff, or nicotine gum and relief of those symptoms
provided by nicotine replacement. Another motivating factor for some abstinent
smokers is an average weight gain of 3-4 kg during the first year after stopping
smoking.
There is evidence that the activation of the extrahypothalamic corticotropin-
releasing factor (CRF)-CRF1 receptor system contributes to negative affect
during nicotine withdrawal. During precipitated nicotine withdrawal in rats,
which is associated with anxiety-like behavior, CRF is released in the central
nucleus of the amygdala (101). CRF activation produces anxiety behavior, and
pharmacological blockade of CRF1 receptors inhibits the anxiogenic effects of
nicotine withdrawal. Withdrawal from other drugs such as alcohol, cocaine,
opioids, and cannabinoids is also associated with activation of the
extrahypothalamic CRF system, suggesting that this is a common mechanism of
affective manifestations of drug withdrawal. Both the hypoactivity of the
dopaminergic system and the activation of the CRF system appear to mediate
nicotine withdrawal symptoms that often precipitate relapse.
NEUROBIOLOGICAL MECHANISMS OF
ACTION
Nicotinic Acetylcholine Receptors
Nicotinic acetylcholine receptors (nAChRs) belong to a superfamily of ligand-
gated ion channels that includes GABA, glycine, and 5-hydroxytryptamine
(serotonin) receptors (12,54). The basic conformational states of a nAChR
channel are the closed state at rest, the open state, and the desensitized state.
After binding the endogenous agonist, acetylcholine (ACh), or an exogenous
agonist, nicotine, the nAChR ion channel enters the open conformation for
several milliseconds. While open, nAChRs conduct cations that cause a local
depolarization of the neuron’s membrane and produce an intracellular ionic
signal. Although sodium and potassium ions carry most of the current through
open nAChR channels, calcium also can make a small but significant
contribution (12). The open pore of the receptor/channel complex then closes to
a resting state or to a desensitized state that is unresponsive to ACh or other
agonists for varying lengths of time, usually in the millisecond to second time
range.
The kinetic rate at which the nicotinic receptor proceeds through the various
conformational states and the selectivity with which it conducts cations in the
open state depend on many factors, including the subunit composition. The
nAChR consists of five polypeptide subunits assembled like staves of a barrel
around a central water-filled pore (54). Various subunit combinations produce
many different nAChR types. Three broad functional classes of nAChRs are
recognized: muscle nAChRs (not discussed here), neuronal nAChRs formed
from alpha and beta subunit combinations (α2-α6 and β2-β4), and neuronal
nAChRs formed only of alpha subunits (α7-α9 or α10 with α9). Some evidence
suggests that subunits of the separate classes are capable of combining to form
nAChRs, but such combinations seem to be less common. Therefore, the
extensive nAChR subunit-combinatorial diversity has the potential to produce
many different responses to endogenous or exogenous agonists. The intensity of
the membrane depolarization, the kinetics of gating activation, the rates of
desensitization and recovery from desensitization, the size of the ionic signal, the
pharmacology, and the regulatory controls of the ACh response all depend on the
subunit composition of the nAChRs. In addition, the local environmental and
regulatory factors influence the function of nAChRs. These influences include
peptide transmitters, various protein kinases, the cytoskeleton, and calcium.
To add further complexity, the three basic conformational states (rest, open,
and desensitized) do not account for the actual kinetic properties of nicotinic
receptors. Rather, there are multiple conformations involved in the gating (102).
Desensitization, in particular, encompasses many time constants. Thus, there
may be short- and long-lived states of desensitization. Long exposures to low
concentrations of agonist will favor deeper levels of desensitization for some
nAChR subtypes, and this situation is often the case for smokers, who maintain
low concentrations of nicotine throughout the day (13,103).
Genetic and neurophysiological studies in mice indicate the α4β2* nAChRs
(where * indicates the potential presence of other nAChR subunits) often in
combination with the α6 subunit are primarily responsible for the initiation of
nicotine addiction (2,13,104). In β2-subunit knockout mice, nicotine is less able
to release DA in the brain, and these animals do not self-administer nicotine.
Genetic manipulation of the α4 subunit alters sensitivity to the effects of nicotine
(105). The expression of somatic withdrawal symptoms mainly depends upon
the α5, α2, and β4 nicotinic subunits (13).
The Cholinergic Systems

Cholinergic neurons release the neurotransmitter, ACh, and project throughout
the CNS, providing diffuse, sparse innervation to practically all of the brain
(12,106). Cholinergic cell bodies are positioned along a loosely contiguous axis
running from the cranial nerve nuclei of the brainstem to the medullary
tegmentum and pontomesencephalic tegmentum, continuing rostrally through
the diencephalon to the telencephalon. Generally, cholinergic projection systems
provide broad, diffuse, and generally sparse innervation to wide areas of the
brain. These systems include the following (12): (a) the pedunculopontine and
lateral dorsal tegmental nuclei, providing widespread innervation to the thalamus
and midbrain dopaminergic areas and also descending innervation to the caudal
pons and brainstem; (b) various basal forebrain nuclei that make broad
projections throughout the neocortex, hippocampus, thalamus, and amygdala. (c)
Another subsystem arises from a collection of cholinergic interneurons located
in the striatum (107–109). Unlike many broadly projecting cholinergic neurons
throughout the brain, these cholinergic interneurons make up ~2% of the striatal
neurons, and they provide very rich local innervation throughout the striatum
and the olfactory tubercle (107–109).
Cholinergic systems have significant complexity beyond nicotinic signaling,
but acting via nAChRs, nicotine or nicotinic cholinergic innervation can increase
arousal, heighten attention, influence stages of sleep, produce states of euphoria,
decrease fatigue, decrease anxiety, act centrally as an analgesic, and influence
cognitive function (106,107,109). It is thought that cholinergic systems affect
discriminatory processes by increasing the signal-to-noise ratio and by helping to
evaluate the significance and relevance of stimuli. These normal brain
cholinergic functions are usurped by nicotine addiction and are believed
somewhat unique and central to why nicotine addiction has perhaps the highest
rate of relapse among addictive drugs.
Nicotinic Mechanisms in the CNS

The most widely observed synaptic role of nAChRs in the mammalian CNS is to
influence neurotransmitter release (12). Presynaptic nAChRs are thought to
initiate a direct and indirect calcium signal that boosts the release of
neurotransmitters. Exogenous application of nicotinic agonists enhances, and
nicotinic antagonists often diminish, the release of ACh, dopamine,
norepinephrine, serotonin, GABA, and glutamate. In many cases, the α7*
nAChRs, which are highly calcium permeable, mediate the increased release of
neurotransmitter, but in other cases, different nAChR subtypes are involved.
Nicotinic AChRs also have roles in neuronal development and plasticity
(12,110,111). The density of nAChRs varies during the course of development,
and nAChRs can contribute to activity-dependent calcium signals. Nicotinic
regulatory, plasticity, and developmental influences may be important in the
etiology of disease. Biological changes that inappropriately alter nicotinic
mechanisms could immediately influence the release of many neurotransmitters
and alter circuit excitability. Moreover, nicotinic dysfunction could have long-
term developmental consequences that are expressed later in life.
The tremendous diversity of nAChRs provides the flexibility necessary for
them to play multiple, varied roles (12,106). Broad, sparse cholinergic
projections ensure that nicotinic mechanisms modulate the neuronal excitability
of relatively wide circuits. Although fast nicotinic transmission (as seen at the
neuromuscular junction) is not the predominant mechanism in the CNS, it can
contribute excitatory input to many synapses at one time. Nicotinic receptors
located on presynaptic terminals or located on axons before the presynaptic
terminals (ie, preterminal) modulate the release of many neurotransmitters. The
activity of nAChRs at those locations induces a local depolarization that may
initiate a local action potential, or the activity may directly or indirectly induce a
calcium signal. Both the local action potential and calcium signal influence
neurotransmitter release if the effects invade active release sites that are most
commonly located in presynaptic terminals. In addition, ACh also diffuses from
release sites depending on the local density of acetylcholinesterase (AChE),
which is the enzyme that breaks down (hydrolyzes) ACh. Although AChE is
widely distributed in the CNS, evidence indicates that the density and location of
AChE do not always match the location of ACh release sites. Consequently,
ACh diffuses and acts at lower concentrations substantial distances away from
the release site in a process called volume transmission. Owing to volume
transmission, nAChRs influence broad circuit excitability owing to nAChR
effects occurring well outside of the synaptic sites (12).
Nicotine Influences on Dopaminergic Neurons

While nicotine is not the only compound contributing to the addictive influence
of tobacco, a great deal of evidence supports that it is the primary addictive
component (2,13,112). Although many areas of the brain participate, the
mesocorticolimbic DA system serves a vital role in the acquisition of behaviors
that are reinforced by addictive drugs. An important dopaminergic pathway
originates in the ventral tegmental area (VTA) of the midbrain and projects to the
prefrontal cortex, as well as to limbic and striatal structures, including the
nucleus accumbens. Blocking DA release in the nucleus accumbens with
antagonists or lesions reduces nicotine self-administration in rodents.
Nicotine Activates and Desensitizes nAChRs

on Mesocorticolimbic Neurons
In rat brain slices, nicotine, at concentrations comparable to those seen in
tobacco users, activates and desensitizes nAChRs on VTA dopamine (DA)
neurons and thereby potently modulates the firing of VTA neurons (2,13,54,112).
Nicotine reaches nAChRs at every brain location, including those at presynaptic,
postsynaptic, and nonsynaptic (including somal) locations. On the DA neuron’s
cell bodies and postsynaptically, the majority of nAChRs contain α4β2 subunits,
and those nAChRs have a high affinity for nicotine. The α4 and β2 subunits are
often in combination with α5 or α6. α4β2-containing (α4β2*) nAChRs also
predominate on inhibitory GABAergic neurons innervating this area. The DA
neurons from the posterior VTA that provide the main projection to the nucleus
accumbens commonly express α6 and β3 with the α4 and β2 subunits (113,114).
At the low concentrations of nicotine achieved by smokers, the presence of the
α6 subunit, particularly in α6α4β2* nAChRs, slows the rate and degree of
desensitization seen with the higher-affinity α4β2 nAChRs (115). Therefore,
those α6-containing receptors are important to maintain the more prolonged
activation of DA neurons caused by nicotine from tobacco (113). In addition,
α4β2* nAChRs containing the α6 subunit regulate DA release in target areas
such as the nucleus accumbens. The α7* nAChRs, which have a much lower
affinity for nicotine, are at lower density in the midbrain (116); they are more
commonly located on the presynaptic terminals of excitatory glutamatergic
afferents into this midbrain area (in rodent studies) (12). This arrangement of
nAChRs is hypothesized to underlie their enhancement of excitatory synaptic
potentiation (12,112).
When nicotine first arrives in the midbrain DA area, it excites nAChRs,
particularly the high-affinity α4β2* nAChRs and related nAChR subtypes and,
to a lesser degree, the lower-affinity α7* nAChRs. Activation of the presynaptic
nAChRs enhances the release of glutamate. The postsynaptic (and somal) α4β2*
nAChRs, including those containing α6, contribute to the depolarization of DA
neurons, helping N-methyl-D-aspartate (NMDA) receptors to participate in
glutamatergic synaptic potentiation (12,13). After the initial exposure to nicotine
and potentiation of glutamatergic afferents, there is significant, but incomplete,
desensitization of the high-affinity α4β2* nAChR subtypes. Particularly owing
to the presence of the α6 subunit in many α4β2* nAChRs as well as more rare
α7* nAChRs, many nAChR subtypes are not strongly desensitized. Some of the
inhibitory GABA transmission decreases, however, because the α4β2 nAChR
subtype is significantly desensitized, and the GABAergic inhibition of the DA
neurons decreases because any afferent cholinergic activity that normally
boosted GABA release no longer can act on all the α4β2* receptor subtypes.
Glutamatergic excitation of the DA neurons remains elevated after nicotine
exposure because the synaptic potentiation that was initiated by nAChR activity
persists for longer time periods (known as long-term synaptic potentiation). In
addition, the presynaptic α7* nAChRs on glutamatergic afferents are much less
desensitized by the low concentrations of nicotine that are present. Therefore,
α7* nAChRs continue to enhance glutamate release, particularly at the
potentiated synapses that provide ongoing excitation of DA neurons
(2,12,13,112). Thus, while a patient may have stopped smoking and is no longer
self-administering nicotine, the effects of nicotine remain in the form of
glutamate-mediated release of DA for as long as 2 months due to long-term
potentiation. This glutamate excitation results in a higher risk for relapse.
Distinct nAChRs subtypes contribute to the manifestations of the withdrawal
syndrome. The withdrawal syndrome is not mediated by the same mechanisms
or by the same neural circuits that initiate addiction or nicotine/tobacco use
disorder. The epithalamic habenular complex and its targets appear to be critical
for the withdrawal syndrome. The medial habenula (MHb) and one of its
primary targets, the interpeduncular nucleus (IPN), richly express β4 and α5
nAChR subunits (and α2 only in the IPN) that are necessary for the
neuroadaptations that lead to somatic withdrawal symptoms during nicotine
abstinence (13,117,118). In mouse models, the absence of α5 or β4 nearly
eliminates the somatic signs of withdrawal. This phenotype is in sharp contrast
with that of β2-lacking mice, which display normal somatic signs of withdrawal
(13,119,120). Another nicotinic subunit that contributes to the somatic signs of
withdrawal is the α2 subunit (118), which is selectively expressed in the IPN and
the olfactory bulb of rodents (121). The α7 subunit plays a smaller role (122).
The α5, α2, and β4 subunits are highly expressed in MHb and IPN (13,123).
Microinjection of the nAChR antagonist mecamylamine into the Hb and IPN
was sufficient to precipitate nicotine withdrawal symptoms in mice chronically
treated with nicotine. Furthermore, mice lacking α5 in the MHb self-administer
nicotine at doses that elicit strong aversion in wild-type mice. This result
suggests that α5-containing nAChRs in the MHb are key to the control of the
amounts of nicotine self-administered (124,125). Taken together, these data
suggest a prominent role of the MHb/IPN axis in mediating nicotine’s aversive
effects and the somatic symptoms of withdrawal (13,118).
The single nucleotide polymorphism (SNP), rs16969968, within CHRNA5
correlates with nicotine addiction risk, heavy smoking, and the pleasurable
sensation produced by a cigarette (11,77,126); it may be hypothesized some
people with that SNP smoke more and become addicted at a younger age
because of less functional activity by α5* nAChRs in the MHb/IPN axis. The
presence of fewer aversive effects (even at higher nicotine doses) during the
initial contact with nicotine would promote the hedonic drive, thereby promoting
the transition from use to tobacco use disorder.
Hypotheses to Extrapolate the Cellular

Results to People Who Smoke
The development and maintenance of nicotine addiction are a combination of
positive reinforcements, including enhancement of mood, and avoidance of
negative factors related to withdrawal symptoms (13,55) (Fig. 14-3). In addition,
there is drug use associated learning that creates smoking-related cues that spur
reinforced behaviors for continued use. That is, nicotine-induced cellular
changes in the brain are like normal learning mechanisms that associate
environmental input (in this case, smoking context and cigarettes) with
behavioral repertoire (in this case, getting and smoking a cigarette).
Figure 14-3 A simplified cycle for continued tobacco use,

based on nicotine’s cellular actions. The nicotinic
acetylcholine receptors (nAChRs) are initially and transiently
activated when nicotine first arrives. The incomplete
desensitization of some nAChR subtypes follows as the
concentration of nicotine is maintained during the day; then,
slowly decreases overnight. The increased number of
nAChRs and other neuroadaptations develop after chronic
use of nicotine. The learned associations occur over the
course of tobacco use as nicotine causes reinforcements of
behavior via the mesocorticolimbic systems. (Adapted from
Dani JA, Heinemann S. Molecular and cellular aspects of
nicotine abuse. Neuron. 1996;16:905-908.)
On the basis of cellular studies of nAChR activation and desensitization, it is

possible to infer some of the effects of smoking cigarettes, each of which
delivers about 20-100 nM nicotine to the brain (7,13,127). Initially, the brain is
free of nicotine, and nAChRs should be responding normally to cholinergic
synaptic activity. When nicotine first arrives, especially high-affinity α4β2*
nAChRs are activated, causing the neurons to depolarize and fire action
potentials. This process has multiple consequences throughout the brain
(13,54,103) (Fig. 14-3). DA neurons are activated, contributing to the increase in
DA that is broadcast throughout the brain via the mesocorticolimbic projections.
Present theories hold that these neuronal events reinforce the behaviors (tobacco
use and associated events) that produce the DA release (2,13,112,128). For
example, the DA signal reaching the memory center of the hippocampus
increases the likelihood to synaptic change as a mechanism for learning the
associated environmental events (eg, the smoking place and context) with the
behavior (eg, smoking a cigarette) that produced the DA signal (95,128). Thus,
smoking and associated behaviors, whether incidental or meaningful, are
reinforced (in a type of learning process) (12,95). As the nicotine from the
cigarette lingers, desensitization of especially high-affinity subtypes of nAChRs
begins. This process decreases the reinforcing effect obtained by smoking
multiple cigarettes in a row. However, the desensitization process is not
complete, and in fact, there is considerable variability in desensitization of the
various nAChR subtypes, and lower-affinity nAChRs, such as those containing
α6 or α7, may show little desensitization owing to the low levels of nicotine.
Nicotinic receptor desensitization has other effects (12,13). When nicotine is
present, the high-affinity nicotine sites (including α4β2* nAChRs) are more
likely to desensitize. At cholinergic synapses, nAChRs experience repeated
exposures to synaptic ACh and are exposed to nicotine from the cigarette. The
combination of agonist exposures increases the probability that these nAChRs at
active cholinergic synapses will desensitize. Thus, smoking will turn down the
gain for information arriving via nicotinic cholinergic synapses because fewer
nAChRs will be able to respond to the released ACh. In summary, nicotine not
only sends inappropriate information through the nicotinic and
mesocorticolimbic DA systems, but it also decreases the amplitude for normal
nicotinic information processing at cholinergic synapses.
Long-term nicotine exposure leads to neuroadaptations; the most well-
known is an increase in the number of mainly high-affinity nAChR subtypes
(14,15,96,129). After long periods (weeks, months, or years) of smoking,
nAChRs dramatically increase in number owing to a number of nicotine-
instigated mechanisms. For example, a coat protein complex I (COPI)-mediated
process contributes to up-regulation of α6* or α4* nAChRs (130). Nicotine
exploits a COPI-dependent process to chaperone high-affinity nAChRs, leading
to increased expression in the cell membrane. In addition, the regulation of
nAChR numbers is complex, involving the ubiquitin–proteasome system that
regulates the stability of neuronal nAChRs (15,131,132). Nicotine reduces
proteasomal activity, which also contributes to the up-regulation of nAChRs and
other synaptic proteins.
When nicotine is removed from the brain during abstinence, some of the
excess nAChRs recover from desensitization, resulting in an excess excitability
of the nicotinic cholinergic systems of people who smoke. This
hyperexcitability, where nAChRs have been up-regulated, could contribute to the
unrest and agitation (nicotine withdrawal) that contribute to the smoker’s
motivation (a.k.a., negative reinforcement) for the next cigarette, which
“medicates” the smoker by desensitizing the excess number of nAChRs back
toward a more normal level.
These receptor changes may underlie the most common pattern of cigarette
smoking. Most smokers report that the first cigarette of the day is the most
pleasurable (13,55,133,134). After a night of abstinence, nicotine concentrations
in the brain are at their lowest level. Thus, smoking the first cigarette most
strongly activates nAChRs (103), possibly causing the largest activity of the
midbrain DA areas and contributing to the most reinforcing effects (Fig. 14-3,
Step 1). After a few cigarettes, there is significant (albeit incomplete)
desensitization, causing some acute tolerance and less effect from additional
cigarettes (Fig. 14-3, Step 2). The process of activation and desensitization
affects different nAChR types differently and influences synaptic plasticity,
contributing to the long-term changes associated with addiction. When smoking
continues for long periods, the nicotinic system undergoes various
neuroadaptations, including an increase in the number of high-affinity nAChRs
(Fig. 14-3, Step 3). Cigarettes are smoked throughout the day, in part, driven by
smaller variable rewards and by the agitation arising from the excess nAChRs
and hyperexcitability at cholinergic synapses experienced during abstinence
(Fig. 14-3, Step 4).
Episodes of cigarette smoking are often separated by hours of abstinence.
During that time, nicotine levels drop, and some nAChRs recover from
desensitization. Smokers often report that cigarettes smoked during the day help
them to focus and relax so that they can work more efficiently (55,134). As an
individual smokes several times during the course of a day, the background level
of nicotine slowly increases. Therefore, a smoker experiences some exposure to
nicotine throughout the day, ensuring that some subtypes of nAChRs visit states
of desensitization. These episodes of nAChR desensitization ensure that the
number of nAChRs becomes and remains elevated (owing to mechanisms of
neuroadaptations). If nicotine is avoided for a few weeks, the number of
nAChRs begins to return to the lower value seen in nonsmokers (12). Although
this readjustment suggests that disease remission may be underway, the nicotine-
associated learning and memory are not extinguished. Thus, smoking-associated
conditioned cues can continue to motivate tobacco use for long periods beyond
this stage.
Importantly, the design of various products (combusted tobacco cigarettes,
snuff, snus, pipes, etc.) that deliver nicotine to the human brain has evolved from
decades of research and careful engineering to enhance addiction liability. These
involve additives and ingredients with chemosensory effects that act
synergistically with nicotine to increase product appeal, improve product
initiation, discourage product cessation, and promote relapse (135,136). These
include, but are not limited to, camouflaging the odor of smoke, increasing the
delivery of free-base nicotine, adding menthol and ammonia, and adding
flavorings (137). Increasingly, similar approaches are being seen with electronic
cigarettes.
Most attempts to quit fail (7,13,69). In fact, most fail before the weeks to
months that it takes for the effects of nicotine on human brain nAChRs and
glutamate-mediated DA release to approach normalization. Over years of
smoking, long-term synaptic changes result in learned associations, including
associations with the events, people, and context in which smoking takes place.
Because these behaviors are repeatedly and variably reinforced by nicotine and
its associated cues (people, places, and things such as cigarettes, lighters, e-
cigarettes, advertising, etc.), these associations become conditioned cues that
motivate tobacco usage, such that the desire for cigarettes extinguishes slowly
and sometimes incompletely. Thus, nicotine leaves an “indelible imprint,” and
desire for cigarettes may be experienced even years after having quit, cued by
learned associations (2,13,99).
Monoamine Oxidase and Tobacco Use

Disorder
Cigarette smoking is associated with reduced activity of the enzymes
monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), as
demonstrated by positron emission tomography scanning of the brain using
MAO substrates (138,139). Inhibition of MAO is produced not by nicotine, but
by condensation products of acetaldehyde with biogenic amines, such as
benzoquinones, 2-naphthylamine, harmon, and other chemicals. The main
function of MAO is to metabolize catecholamines, including DA. Inhibition of
MAO would be expected to result in higher brain levels of DA after exposure to
nicotine. Studies in rats show that pretreatment with drugs that inhibit MAO
make nicotine more rewarding and increase the likelihood and rate of acquisition
of nicotine self-administration (140). Therefore, MAO inhibition may contribute
to the addictiveness of smoking. In addition, given that medications that inhibit
MAO have antidepressant action, smoking-induced inhibition of monoamine
oxidase might contribute to the perceived benefit of smoking by some depressed
patients.
SYSTEMIC TOXICITY
Particulate and Gaseous Components of

Tobacco Smoke
Tobacco smoke is composed of volatile (gaseous) and particulate phases that
contain substances other than nicotine that are primarily responsible for human
morbidity and mortality. The volatile phase contains more than 500 gaseous
compounds, including nitrogen, CO, carbon dioxide, ammonia, hydrogen
cyanide, acrolein, butadiene, and benzene. There are about 3500 different
compounds in the particulate phase, including the pharmacologically active
alkaloids nornicotine, anabasine, anatabine, myosmine, nicotyrine, and nicotine.
Assays for some of these alkaloids are used as biomarkers of tobacco use (46).
The “tar” in a cigarette is composed of the particulate matter minus its alkaloid
and water content. Tar contains many carcinogens, including polynuclear
aromatic hydrocarbons, N-nitrosamines, and aromatic amines. The U.S. Surgeon
General’s office recently published a nearly one thousand page review of the
health consequences of smoking (6).
Cardiovascular, Pulmonary, and Oncological

Toxicities
Smokers are exposed to more than 7000 different chemicals, including at least
50 known carcinogens (141). The increased risk of cardiovascular disease
among cigarette smokers likely is related to exposure to oxidant chemicals,
particulates, and CO, as well as acrolein, hydrogen cyanide, carbon disulfide,
cadmium, and zinc (142). Although CO reduces oxygen delivery to the heart,
oxidant chemicals are primarily responsible for endothelial dysfunction, platelet
activation, thrombosis, and coronary vasoconstriction (143).
Cigarette smoking has significant detrimental effects on both the structure
and function of the lung. Cigarette smoking causes an imbalance between
proteolytic and antiproteolytic forces in the lung and heightens airway
responsiveness. Chronic obstructive lung diseases are linked with exposure to
tar, nitrogen oxides, hydrogen cyanide, and volatile aldehydes, enhanced by
inducers of superoxide and H2O2 (144).
The agents contributing most significantly to lung cancer are thought to be
the carcinogenic polynuclear aromatic hydrocarbons and the tobacco-specific N-
nitrosamines, followed by polonium-210 and volatile aldehydes. Catechol, the
weakly acidic agents, volatile aldehydes, and nitrogen oxides that can serve as
precursors in the exogenous and endogenous formation of N-nitrosamines
enhance tobacco smoke-induced tumorigenesis (145). Active smokers with
elevated levels of DNA damage from polynuclear aromatic hydrocarbons in their
white blood cells (DNA adducts) are three times more likely to be diagnosed
with lung cancer 1-13 years later than are smokers with lower adduct
concentrations (odds ratio, 2.98; 95% confidence interval, 1.05-8.42; p = 0.04)
(146). As with other tobacco-related diseases, the risk of cancer of the mouth,
larynx, esophagus, lung, stomach, pancreas, kidney, urinary bladder, and uterine
cervix as well as leukemia is directly related to the intensity and duration of
exposure to cigarette smoke and to nicotine, which is itself a tumor promoter.
Other Physiological Effects and Toxicities

Cigarette smoking is associated with skin changes, including yellow staining of
fingers, vasospasm and obliteration of small skin vessels, precancerous and
squamous cell carcinomas on the lips and oral mucosa, and enhanced facial skin
wrinkling. Tobacco smoke and exposure to ultraviolet A radiation each cause
wrinkle formation. When excessive sun exposure (>2 hours per day) and heavy
smoking (>35 pack years) occur together, the risk of developing wrinkles is 11.4
times higher than that of nonsmokers and those with less sun exposure at the
same age (147). The induction of matrix metalloproteinase-1, mediated by
reactive oxygen species (especially in people with low glutathione content
fibroblasts), is thought to be an important mechanism underlying premature skin
aging caused by cigarette smoking and exposure to ultraviolet A radiation.
Current smokers of 20 or more cigarettes per day have statistically
significant increases in nuclear sclerosis and posterior subcapsular cataracts
compared with individuals who never smoked. After adjusting for age and
average number of cigarettes smoked per day, former smokers who had quit
smoking 25 or more years previously have a 20% lower risk of cataracts, but still
higher than among subjects who never smoked (148). Current smokers of more
than 20 cigarettes per day also have an increased risk of age-related macular
degeneration (149).
Cigarette smoking in women is associated with lower levels of estrogen,
earlier menopause, and increased risk of osteoporosis (150). The alkaloids in
tobacco smoke diminish estrogen formation by inhibiting an aromatase enzyme
in granulosa cells or placental tissue.
In men, smoking may impair penile erection, primarily in those with
underlying vascular disease, through the impairment of endothelium-dependent
smooth muscle relaxation (151). Smoking doubles the likelihood of moderate or
complete erectile dysfunction associated with other risk factors, such as coronary
artery disease and hypertension. Because the prevalence of erectile dysfunction
in former smokers is no different from that in individuals who never smoked,
erectile dysfunction is believed to improve with stopping smoking (151).
Nicotine both suppresses appetite and increases metabolic rate (152,153).
Smokers weigh an average 2.7-4.5 kg (6-10 lb) less than nonsmokers. After
stopping smoking, individuals typically crave sweets. Individuals who stop
smoking typically gain weight to approximately the levels of never smokers in
the 6-12 months after stopping smoking.
Through release of catecholamines, nicotine increases lipolysis and releases
free fatty acids, which are taken up by the liver (154). This could contribute to
the increase in very low-density lipoprotein and low-density lipoprotein and the
decrease in high-density lipoprotein seen in smokers.
Cigarette smoking is associated with the occurrence and delayed healing of
peptic ulcers. Mechanisms include decreases in the mucous bicarbonate barrier
in the stomach, reduction in the production of endogenous prostaglandins in the
gastric mucosa, and increased proliferation of Helicobacter pylori (155).
Tobacco and Pregnancy

Smoking during pregnancy and lactation has been associated with a variety of
untoward child health outcomes, including preterm birth, fetal growth restriction,
low birth weight, sudden infant death syndrome, neurodevelopmental and
behavioral problems, obesity, hypertension, type 2 diabetes, impaired lung
function, asthma, and wheezing (156,157). Nicotine itself has been implicated as
at least partially causative for a number of these adverse outcomes from
maternally derived exposures to smoking (158). Smoking during pregnancy
nearly doubles the relative risk of having a low-birth-weight infant; the relative
risks of spontaneous abortion and perinatal and neonatal mortality are increased
by about one-third (159). The components of tobacco smoke responsible for
obstetric and fetal problems have not been definitively identified. CO clearly is
detrimental because it markedly reduces the oxygen-carrying capacity of fetal
hemoglobin (160). The use of smokeless tobacco, which delivers nicotine but
not combustion products, during pregnancy is associated with an increased risk
of pre-eclampsia, while smoking during pregnancy is protective against pre-
eclampsia. It is hypothesized that carbon monoxide in cigarette smoke acts as a
vasodilator to counter the vasoconstrictor effects of nicotine, while in smokeless
tobacco and perhaps electronic cigarette users, the nicotine effects are
unopposed, leading to arteriolar vasoconstriction and hypertension, as seen in
pre-eclampsia.
The effect of smoking in lowering birth weight interacts with the metabolic
genes CYP1A1 and GSTT1 (159). Infants born to smoking mothers who had
genetic variants associated with reduced CYP1A1 activity—Aa and aa
(heterozygous and homozygous variant types)—and reduced or absent GSTT1
activity had greater reductions in birth weight than did infants born to smoking
mothers who had the normal metabolic activity genes CYP1A1 AA
(homozygous wild type) or GSTT1 genotype. The CYP1A1 and GSTT1
enzymes have roles in metabolizing and excreting some toxic chemicals in
cigarette smoke.
In the developing fetus, nicotine can arrest neuronal replication and
differentiation and can contribute to sudden infant death syndrome (161).
Nicotine activates nicotinic cholinergic receptors in the fetal brain, resulting in
abnormalities of cell proliferation and differentiation that lead to shortfalls in cell
numbers and eventually to altered synaptic activity. Comparable alterations
occur in peripheral autonomic pathways and are hypothesized to lead to
increased susceptibility to hypoxia-induced brain damage, perinatal mortality,
and sudden infant death (28,159,161).
Secondhand Smoke
Secondhand smoke (SHS) is the complex mixture formed by the escaping smoke
of a burning tobacco product, as well as smoke that is exhaled by a smoker.
Sidestream smoke contains higher concentrations of some toxins than does
mainstream smoke. SHS characteristics change as it combines with other
constituents in the ambient air and ages (162). Exposure to SHS is causally
associated with acute and chronic coronary heart disease, lung cancer, nasal
sinus cancer, and eye and nasal irritation in adults and with asthma, chronic
respiratory symptoms, acute lower respiratory tract infections such as bronchitis
and pneumonia in children, and potentially certain psychiatric disorders (162).
SHS also is causally associated with low birth weight and sudden infant death
syndrome in infants (162). Young children’s exposure to tobacco smoke comes
mainly from people who smoke in the home, especially parents. Maternal
smoking has the greatest effect on children’s measured cotinine levels (162).
Additional contributors include paternal smoking, smoking by other household
members, and smoking by child care personnel.
An average salivary cotinine level of 0.4 ng/mL corresponds to an increased
lifetime mortality risk of 1/1000 for lung cancer and 1/100 for heart disease
(163). Assuming a prevalence of 28% for unrestricted smoking in the workplace,
passive smoking would yield 4000 heart disease deaths and 400 lung cancer
deaths annually in the United States. More than 95% of SHS-exposed office
workers exceeded the significant risk level for heart disease mortality, and more
than 60% exceeded the significant risk level for lung cancer mortality
established by the Occupational Safety and Health Administration (163).
Morbidity and Mortality

The cumulative result of these health effects is that each pack of cigarettes sold
in the United States costs the nation an estimated $7.18 in medical care
expenditures and lost productivity (164). Tobacco use is a leading cause of death
in the United States, causing more than 480,000 deaths per year (2–5), which is
about one in every five deaths (6). This includes 148,605 deaths (36.9%) from
cardiovascular causes, 155,761 deaths (38.7%) from cancer, and 98,008 deaths
(24.3%) from nonmalignant pulmonary disease (164). Cigarette smoking also
increases the risk of developing and increases the severity of respiratory tract
infections, including influenza, pneumococcal pneumonia, and tuberculosis
(165). On average, adult men and women who smoke lost 13.2 and 14.5 years of
life, respectively, due to smoking. In contrast, the annual mortality attributable to
passive smoking between 1995 and 1999 was estimated at 39,060 deaths,
including 35,053 from cardiovascular diseases, 3000 from lung cancer, and 1007
from perinatal conditions (5,164).
Nicotine and Other Addictions

There is a strong association between smoking and alcohol use disorder (2,93).
People who are more severely addicted to alcohol smoke more and are less
likely to quit. Tobacco also synergizes with alcohol in causing a number of
medical complications. Smoking and heavy drinking, in combination, are
associated with substantially increased rates of oral and esophageal cancers (6).
Because lit cigarettes smolder when they fall onto upholstered furniture, alcohol
use combines with smoking to cause household fires that claim more than 1000
lives per year among children and adults (166). Persons recovering from other
substance use disorders often die from tobacco-related illnesses. In a landmark
population-based retrospective cohort study, death certificates were examined for
214 of 854 persons who were admitted between 1972 and 1983 to an inpatient
program for the treatment of alcoholism and other non-nicotine potentially
addicting substances (167). Of the deaths reported, 50.9% were caused by
tobacco use, whereas 34.1% were attributable to alcohol use. The cumulative 20-
year mortality was 48.1% versus an expected 18.5% for a demographically
matched control population (p < 0.001).
Benefits of Stopping Smoking

Most smokers (>70%) want to quit, and approximately 40% attempt to quit each
year. However, without assistance, only about 2%-5% of the attempts are
successful (7). The good news is that stopping smoking has benefits for smokers
of all ages. The immediately decreased risk of cardiovascular death in those who
stop smoking may reflect a decrease in blood coagulability, improved tissue
oxygenation, and reduced predisposition to cardiac arrhythmias. Among former
smokers, the reduced risk of death compared with continuing smokers begins
shortly after quitting and continues for at least 10-15 years. After 10 to 15 years’
abstinence, the risk of all-cause mortality returns nearly to that of persons who
never smoked (168).
ACKNOWLEDGMENTS
During the writing of this chapter, JAD was supported by the National Institutes
of Health NS21229, DA036572, and DA09411; and NLB was supported by the
National Institutes of Health and Food and Drug Administration Center for
Tobacco Products grant P50CA180890.
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CHAPTER 15
The Pharmacology of Cannabinoids
Sandra P. Welch, Tricia H. Smith, Robert Malcolm, and
Aron H. Lichtman
CHAPTER OUTLINE
Introduction
Substances Included
Formulations
Synthetic Cannabinoids
Historical Features
Epidemiology
Cannabinoid Receptor Neurobiology
Endocannabinoid System
Endocannabinoid Signaling
Nonclinical Use
INTRODUCTION
Cannabis sativa, historically, is one of the oldest and most widely used plants in
the world as a source of various products including the drug ∆9-
tetrahydrocannabinol (THC) (1). The discovery of cannabinoid receptors and of
the endocannabinoid system (ECS) altered in an explosive way the direction of
research on cannabinoids, moving the study of the exogenous administration of
natural plant products to that of the multiple homeostatic mechanisms
maintained by the generation of endogenous cannabinoids in the human and,
subsequently, the clinical implications of modulation of this phylogenetically
ancient and widely abundant receptor system, as discussed in this chapter (2).
SUBSTANCES INCLUDED
THC, the major psychoactive ingredient in the cannabis plant, first was isolated
and purified in 1965 (3). This important discovery was the first step in
elucidating the site and mechanism of action of the cannabinoids—a general
term for all compounds from the cannabis plant. More than 565 chemicals (4)
are synthesized by the cannabis sativa plant, ~120 of which are termed
“cannabinoids” due to the chemical structure based on a 21-carbon THC-like
skeleton and include several nonpsychoactive products that have effects that are
clinically useful, such as those of cannabinol and cannabidiol to be discussed in
detail later in this chapter. In addition to the “cannabinoid” structure to date, an
additional 419 non-“cannabinoids” that are of numerous chemical classes have
been discovered. The reader is referred to the chapter by ElSholy et al. (4) for a
comprehensive discussion of the chemical components, structures, and synthesis
of the “cannabinoid” and “noncannabinoid” chemical components present in the
cannabis sativa plant.
Four decades of the investigation of the complex pharmacological properties
of THC culminated in the discovery of neuronal cannabinoid receptors, which in
turn stimulated the search for endogenous ligands for cannabinoid receptors (5).
Endogenous ligands that bind to cannabinoid receptors include
arachidonoylethanolamide (anandamide), 2-arachidonoylglycerol (2-AG),
noladin ether, virodhamin, and N-arachidonoyldopamine. These lipid-signaling
molecules are referred to as endocannabinoids.
There are two known cannabinoid receptor subtypes, CB1 and CB2.
However, emerging evidence for additional cannabinoid receptors is presented
later in this review. The discovery of the receptors led to the development of
numerous synthetic receptor agonists and antagonists, some of which have
medicinal benefit. These include the CB1 cannabinoid antagonist/inverse
agonist, SR141716A (rimonabant), and the cannabinoid CB2 receptor antagonist,
SR144528 (5). Sativex (a 1:1 mixture of THC and cannabidiol) has been
approved to treat spasticity from multiple sclerosis (MS) by Health Canada, the
United Kingdom, and other countries around the world. A mixed ratio of THC
and cannabidiol in capsular formulation produced by Cannador (Cannador,
European Institute for Oncology and Immunological Research, Germany) is also
available. In addition, synthetic ∆9-THC (dronabinol, Marinol) is available, as is
nabilone (Cesamet), a synthetic cannabinoid with therapeutic use as an
antiemetic, appetite stimulant, and adjunct analgesic for neuropathic pain.
Nabilone is a structural analog of THC but produces minimal euphoria. Both
dronabinol and nabilone are marketed as Schedule III preparations (6).
Numerous synthetic cannabinoids of diverse structures continue to be available
for preclinical research purposes only, although the recreational use of such
substances by humans has become widespread and is illegal in all 50 states in the
United States. Such substances are discussed later in this chapter. Four decades
of the investigation of the complex pharmacological properties of THC
culminated in the discovery of neuronal cannabinoid receptors, which in turn
stimulated the search for endogenous ligands for cannabinoid receptors (5,7).
FORMULATIONS
Natural Plant-Derived Cannabinoids

The concentration of THC varies among three common preparations from the
cannabis plant: marijuana, hashish, and hash oil. Marijuana is prepared from the
dried flowering tops and leaves of the harvested plant. Potency decreases
through the upper leaves, lower leaves, stems, and seeds. THC concentrations in
marijuana containing mostly leaves and stems range from 0.5% to 5%. On the
other hand, a fourth preparation from the cannabis plant comes from
“sinsemilla,” the flowering tops from unfertilized female plants, and may have
THC concentrations of 7%-14%. Hashish, dried cannabis resin and compressed
flowers, has 2%-8% THC content. Hash oil obtained by extracting THC from
hashish (or marijuana) with an organic solvent is a highly potent substance with
THC concentration between 15% and 50%. In addition, the extraction of THC
with butane produces a product called BHO or “dab.” The use is termed
“dabbing.” BHO is a concentrated version of hash oil and can contain up to 90%
THC, and production is associated with severe burns or lung injury (8). The
fibrous “hemp” form of cannabis has low THC content (typically <0.4%)
coupled with high cannabidiol content. Marijuana is usually smoked by various
methods. It is frequently rolled into cigarette paper and smoked as a “joint.”
Another ancient and contemporary method of smoking marijuana is in a water
pipe, a “bong.” Cigars are sometimes hollowed out and filled with marijuana.
These are often called “blunts.” Occasionally, tobacco cigarettes will have
hashish resin oil dripped on them and then smoked. Marijuana may be placed in
cookies, brownies, or cakes and ingested orally and absorbed via the
gastrointestinal tract. Synthetic marijuana is generally smoked by one of the
methods just noted, although it can also be packed into metal or glass cylinders
and smoked. In addition, marijuana is often vaporized (“vaping”) to decrease the
generation of the smoke that is perceived as containing more harmful chemicals
than the vapor or aerosol (6).
SYNTHETIC CANNABINOIDS
Synthetic ∆9-THC (dronabinol, Marinol) is available, as is nabilone (Cesamet), a
synthetic THC analogue with therapeutic use as an antiemetic, appetite
stimulant, and adjunct analgesic for neuropathic pain. Nabilone is a structural
analog of THC but produces minimal euphoria. Both dronabinol and nabilone
are marketed as Controlled Substances Act (CSA) Schedule III preparations in
the United States. An oromucosal spray, nabiximols, containing an extract of
cannabis sativa is approved for use in Canada, New Zealand, and elsewhere in
Europe (6). In addition, several European suppliers of THC or THC/CBD
extracts from cannabis extracts are currently licensed to distribute products
within Europe.
Synthetic cannabinoid-like compounds represent a diverse group of
pharmacological agents that are agonists or partial agonists at endogenous CB1
receptors. These agents were originally developed over the last four decades as
pharmacological tools to study the ECS in preclinical models and/or as
therapeutic agents for pain management and other clinical uses recently
reviewed (9–11). The synthetic cannabinoids in general have a higher affinity for
cannabinoid receptors, have active metabolites that prolong their durations of
action and increase accumulations in the body, and have increased potential for
toxicity. The synthetic cannabinoids are predominantly full agonists at the CB1
and CB2 receptors in tests of intrinsic activity such as intracellular signaling
through cyclic adenosine monophosphate (cAMP). THC alone is a partial
agonist at cannabinoid receptors in terms of both potency and efficacy in in vitro
studies (9). Beginning possibly as early as the mid-2000s in Europe and later in
this decade in North America, entrepreneurs began manufacturing substantial
quantities of synthetic cannabinoids. Synthetics are sprayed on herbal plants for
sale on the Internet, head shops, convenience stores, and gas stations. They are
disingenuously marketed as “natural, legal, and herbal” marijuana. They are sold
under names such as Spice, K2, Kush, Potpourri, Skunk, Aroma, Moon Rocks,
Fake Marijuana, and Genie and many rapidly changing names. A number of
these compounds have not been characterized or scheduled as control substances
by the Drug Enforcement Administration. They are not detected in standard
urine drug screens, and distribution methods occur outside of traditional illicit
drug sales networks. These factors have made understanding of the
epidemiology and clinical consequences difficult.
Herbal plant ingredients of synthetic marijuana products are diverse, and
some of these botanicals have psychoactive effects. Indian warrior (Pedicularis
densiflora), rose hip (Rosa canina), dwarf skullcap (Scutellaria nana), and beach
bean (Canavalia maritima) are a few of the dozen or more herbs identified in
synthetic marijuana products. Labels may or may not identify them; the synthetic
marijuana ingredients are usually not listed. The European Union has classified
synthetic marijuanas into four groups (12). The groups include the
cyclohexylphenols, the two structural synthetic drug families produced by J. W.
Huffman, and the fatty acid derivatives. Pfizer in the 1970s created several
cyclohexylphenols that have cannabinoid activity. In the 1990s, J.W. Huffman
and colleagues at Clemson University made a large group of synthetic
compounds with cannabinoid effects. These include JWH-018, JWH-398, and
JWH-250. The latter agent has been identified as a common ingredient of
“Spice” in Germany. The fourth family of compounds is fatty acids, similar to
oleamide, which has a structure similar to anandamide (AEA). These also have
been found in synthetic marijuanas.
HISTORICAL FEATURES
The use of cannabis dates back over 12,000 years (13). Cannabis use is believed
to have started in Central Asia and continued to flourish in Southeast Asia and
India. The ancient Chinese and Greeks made clothes and rope from hemp. It is
believed that cannabis was introduced into the Americas in the 1600s by the
English settlers and Spanish conquistadors. Cannabis was cultivated early in
American history for its fiber. Medicinally, it has long been used in China, India,
the Middle East, South America, and South Africa. The earliest references to its
medicinal uses date back to 2700 BC. Uses in ancient China included treatment
for constipation, malaria, rheumatic pains, and female disorders. The euphoric
properties were discovered in India around 2000 BC, and cannabis was
recommended for reducing fevers, producing sleep, stimulating the appetite,
relieving headaches, and curing venereal diseases. The medicinal uses of
cannabis in Azerbaijan are described in medieval texts from as early as the ninth
century; uses for the drug in modern medicine, some based on folkloric uses,
have been proposed. In 1842, William O’Shaughnessy (14), a British army
physician in India, published a review on the use of cannabis in the treatment of
various medical conditions. Several of these early references to the medical uses
of marijuana include disease states on which research continues today.
Recreational use of cannabis began to surge in the 1930s. Cannabis was
recognized as a legitimate medication and listed in the U.S. Pharmacopoeia from
1850 to 1942; its medical use in the United States was essentially abolished in
1937 by enactment of the Marijuana Tax Act. Cannabis was placed in Schedule I
of the U.S. Controlled Substances Act in 1970. A dramatic increase in cannabis
use was observed during the 1960s, which led to extensive research in the field
of cannabinoid pharmacology (1).
EPIDEMIOLOGY
The use of marijuana/hashish by 12th, 10th, and 8th grade students in the United
States over their lifetime, for the past year prior to the survey and the past month
prior to the survey, is ~46%, 36%, and 23%, respectively, and is exceeded only
by the use of alcohol based upon the most recent National Institute on Drug
Abuse (NIDA) Monitoring the Future Study and represents a small increase
(about 1%) over the percentage use in 2015 (15). In addition, there has been a
significant decline in past-year use of synthetic cannabinoids since the survey
has been tracking its use. In 2016, 22.5 percent of high school seniors used
marijuana in the past 30 days compared with 10.5% who smoked cigarettes. In
2016, daily cigarette use (4.8%) was lower than daily marijuana use (6%) among
high school seniors. The perception of harmfulness, a reliable indicator of future
use, continued a declining trend (15). According to the World Drug Report from
2016 published by the United Nations (UN) (16), ~3.8% of population in 2014
worldwide (183 million people) used cannabis, which takes into account the
potential for a relatively margin of error in any worldwide measures. The UN
Report concludes that cannabis is the most widely consumed drug worldwide.
North and South America represent the largest markets for cannabis (based upon
the seizures of cannabis of nearly 75% of all worldwide) followed by Africa
(14%) and Europe (6%). Information on marijuana use patterns in the United
States is based in part on the National Survey on Drug Use and Health (NSDUH)
(17), a community-based sample of civilian, noninstitutionalized individuals
aged 12 years and older residing in the United States. Individuals excluded from
the survey were homeless individuals not living in shelters, active-duty military
personnel, and residents of institutions such as prisons, jails, nursing homes,
psychiatric hospitals, and long-term residential care facilities. An estimated 22.2
million Americans aged 12 or older in 2014 were past-month users of marijuana.
The percentage of people aged 12 or older who were current marijuana users in
2014 was higher than the percentages from 2002 to 2013. Data on severe or
acute effects of cannabis use come from the Drug Abuse Warning Network,
which abstracts records of almost 1000 emergency departments (EDs) in 48
locations in the United States, primarily in urban areas (18). In 2010, ED visits
for marijuana-related clinical problems increased by 64%, or 179 409 more
visits, over 2004. Marijuana was the second most commonly reported illicit drug
(after cocaine) for all age groups: 149 per 100 000 patient visits versus 210 per
100 000 patient visits, respectively.
Synthetic cannabis use and the variety of synthetic cannabinoids currently
available have recently been reviewed (9,10,19). The prevalence of use of the
synthetic drugs based upon the most recent Monitoring the Future data (15)
indicates that in the United States ~17% of adults had used the synthetic drugs.
In addition, the drugs are used by children surveyed in grades 8-12 with use rates
of 3.1%-5.3% that are higher than for other illicit drugs such as heroin (19). A
voluntary, self-selected, Internet-based survey was completed by 168 individuals
in 13 countries and 42 US states (20). Of those completing the survey, about
80% were male and 90% Caucasian. About 90% purchased synthetic
cannabinoids at gas stations, convenience stores, and head shops. A very high
proportion of synthetic cannabinoid users also used alcohol, marijuana, and
nicotine regularly. Thirty-seven percent met the DSM-IV-TR (21) criteria for
synthetic cannabis abuse; 12% met criteria for DSM-IV-TR cannabis
dependence. Patterns of marijuana use may change as more states alter laws
regarding recreational marijuana legalization, possession, and medical use. As of
December 2016, cannabis use for medical purposes is legal in 33 states and the
District of Columbia (another 17 states have legalized only very low THC
cannabis [ie, cannabidiol]).Nonmedical “recreational” use is legal in 7 states and
the District of Columbia (22,23).The U.S. Drug Enforcement Administration
classifies marijuana and all cannabinoids as Schedule 1 drugs, meaning that they
have “no currently accepted medical uses in the United States and high potential
for abuse” (24). This classification makes marijuana and all plant-derived
cannabinoids illegal at the US federal level, regardless of any state laws
legalizing marijuana for medicinal or recreational purposes.
CANNABINOID RECEPTOR
NEUROBIOLOGY
Cannabinoid Receptors
Cannabinoid receptors exist in two recognized isoforms: cannabinoid receptor 1
(CB1), highly expressed in certain brain regions, and cannabinoid receptor 2
(CB2), associated with immune cells, although both subtypes are abundant in a
variety of other tissues (25). The discovery of the CB1 receptor was fueled by
interest in Δ9-THC, the prototypical cannabinoid and major psychoactive
component in marijuana. An antagonist for the CB1 receptor was discovered:
SR141716A (rimonabant) (25,26)
CB1 receptors are abundant in the brain and highly expressed in the
hippocampus, amygdala, cerebral cortex, basal ganglia, and cerebellum. The
functions of these brain regions are heavily impacted by marijuana use, causing
effects on memory, emotionality, higher cognitive functions, movement, and
body homeostasis. CB1 receptors have major impacts on other bodily systems
and are also found in adipose, liver, gastrointestinal, cardiovascular, skeletal,
bone, pancreas, eye, and male/female reproductive tissue (25,27).
CB1 receptor knockout mice studies demonstrated that the main
pharmacological responses to Δ9-THC, including the addictive properties of
cannabinoids, are almost completely mediated by the CB1 receptor (5,28). The
cannabinoid CB1 receptor is the major player in the behavioral effects of
cannabis and THC across a range of species, including reward, subjective
effects, and the development of dependence and withdrawal, including the
maintenance of chronic marijuana smoking in humans (29). Chronic activation
of the CB1 receptor by THC is required for the development of tolerance and
physical dependence to THC (29,30).
The CB2 receptor was first identified on splenic macrophages. It is found in
both peripheral and central (brain) sites (5,26). The CB1 and CB2 receptors share
40% homology; Δ9-THC has similar binding affinity for both receptor subtypes.
Mechanism of Action
In 2016, x-ray crystallography revealed the gorgeous 3D structure of the human
CB1 receptor (31). This G protein–coupled receptor (GPCR) is coupled to G
proteins, mainly Gi/Go and in certain circumstances, Gs and Gq (Fig. 15-1).
Activation of Gi/Go proteins inhibits adenylate cyclase, while activation of Gs
proteins stimulates adenylate cyclase (5,26). Inhibition of adenylyl cyclase (AC)
decreases cAMP accumulation. CB1-activated G proteins can couple to
phospholipase C (PLC) and ion channels, inhibiting voltage-dependent N- and
P/Q-type Ca+2 channels, activating inward-rectifying K+ channels, and activating
an A-type outward potassium channels. Collectively, the effects on ion channels
serve to decrease neuronal excitability (32). CB1 activation can also trigger
several cell signaling pathways, including mitogen-activated protein kinases
(MAPK), c-Jun N-terminal kinase (JNK), nitric oxide (NO), and a variety of
other cascades. Cannabinoids inhibit an omega-conotoxin–sensitive, high-
voltage–activated N-type calcium channel (32). For reviews, see (26,33).
Figure 15-1 Cannabinoid (CB1) receptor signaling pathways.
Activation of the cannabinoid type 1 (CB1) receptor leads to
the direct activation of inhibitory Gi/o proteins. Gi/o proteins
activate inward-rectifying K+ channels and inhibit voltage-
dependent Ca+2 channels, leading to a decrease in neuronal
excitability. Gi/o proteins inhibit AC activity, which prevents
cyclic AMP (cAMP) formation and reduces the production of
protein kinase A (PKA). Gi/o proteins also activate
phospholipase C (PLC), increasing intracellular protein
kinase C (PKC) activity. Furthermore, CB1 receptors activate
various mitogen-activated protein kinases (MAPKs),
potentially through protein kinase B (PKB, Akt) and other
cascades. Major overall effects on the body are listed in the
insert.
The activation of G proteins by G protein–coupled receptors can be directly

measured using receptor-stimulated binding of the hydrolysis-resistant GTP
analog [35S]GTPγS in membranes and tissue sections. Ligand-activated GPCRs
recruit [35S]GTPγS, creating a radioactive signal that can be measured using a
scintillation counter (34). The receptor specificity of agonist-stimulated
[35S]GTPγS binding has been confirmed by demonstrating specific anatomical
localization corresponding to receptor distribution, antagonist reversibility of the
response, and concentration-dependent and saturable nature of stimulation.
Interestingly, these studies show that cannabinoids are constitutively active,
which means they tonically activate G proteins in the absence of an agonist.
Therefore, CB1 receptors have an intrinsic physiological tone, which may be
thrown out of balance when exogenous cannabinoids are used.
Agonist-stimulated [35S]GTPγS binding also measures desensitization of
cannabinoid receptors following chronic agonist treatment and agonist efficacy
(maximal stimulation) (34). Interestingly, [35S]GTPγS studies demonstrate that
Δ9-THC is a weak agonist; maximally effective doses can only activate the
receptor to ~20% of its full capacity. However, synthetic cannabinoids, such as
WIN55,212-2 and CP55,940, can fully activate the receptor (35). Thus, synthetic
cannabinoids activate significantly more G proteins than THC, which may lead
to the enhanced toxicity seen during use and unhealthy of these compounds, to
be discussed later in this chapter.
Protein phosphorylation plays an important role in the intracellular
modulation of enzymes by both cannabinoids and endocannabinoids. Mitogen-
activated protein kinase, whose activity is increased by CB1 receptor activation,
catalyzes protein phosphorylation. MAPK pathways, such as ERK 1 / 2, are
activated by cannabinoids through a variety of mechanisms, including Gi/o
activation, phosphatidylinositol 3-kinase (PI3K), and inhibition of cAMP and/or
PKA (36). MAPK pathways are also activated by PI3K/PKB (Akt), which in
turn mediates tyrosine phosphorylation and activation of Raf (33).
Cannabinoids activate the inositol phospholipid pathway by activating a G
protein that in turn activates PLC. PLC cleaves phosphatidylinositol 4,5-
bisphosphate (PIP2) into inositol triphosphate (IP3) and DAG. DAG activates
protein kinase C (PKC); IP3 triggers calcium release from intracellular stores,
which may have a myriad of cellular effects.
The CB2 receptor, like the CB1 receptor, is coupled to Gi proteins, inhibits
adenylate cyclase, and activates MAP kinase. The proposed pathway is
activation of PI3K/PKB, which in turn induces translocation of Raf-1 to the
membrane and phosphorylation of p42/p44 MAP kinase. The CB2 receptor
induces the expression of genes through a PKC-dependent activation of MAP
kinase (37).
ENDOCANNABINOID SYSTEM
The behavioral effects of the first endocannabinoid discovered, AEA, are
comparable to those of other psychoactive cannabinoids and cross-tolerant with
other cannabinoids (5,26). AEA is one of a family of arachidonic acid
derivatives that have effects at the cannabinoid receptors. Another major
endocannabinoid is 2-AG, discovered in the canine gut. 2-AG levels are higher
in the brain than are those of AEA.
AEA binds to both CB1 and CB2 receptors, as well as GPR55, which has
recently been classified as a potential cannabinoid receptor, among others (for
reviews, see Refs. (36,37)). The endogenous ligand for the GPR55 is
lysophospholipid (LPL) released from membrane phospholipids via
phospholipase A2. Increasing information on the role of GPR55 and the
discovery of its endogenous agonist, LPL, have stimulated research on the
detection of GPR55 as a risk factor for cancers and metastasis (38).
Endogenous cannabinoids (anandamide, 2-AG) and exogenous cannabinoids
(THC) produce their psychoactive effects by binding to CB1/2 receptors.
Investigations using CB1 knockout mice show that CB1 receptor activation is
necessary for antinociception, decreased spontaneous activity, and other
psychopharmacological effects. Some CNS effects of the cannabinoids are
bidirectional. For example, THC, synthetic cannabinoids, and the
endocannabinoids can either stimulate or inhibit nitrous oxide formation (37).
Synthetic and Degradative Enzymes

AEA and 2-AG are synthesized “on demand” following cell depolarization or
the mobilization of intracellular calcium stores (Fig. 15-2). The process requires
activation of Gq/G11 protein–coupled receptors. Several synthetic pathways for
AEA and 2-AG are now worked out (5,26). Multiple enzymes are involved in
the biosynthesis, transport, and degradation of endocannabinoids, with the
transport proteins being a subject of intense interest and contention (for an
excellent recent review, see (39)).
Figure 15-2 Endocannabinoid synthesis and degradation.

Endocannabinoids, anandamide (AEA) and 2-
arachidonylglycerol (2-AG), are synthesized on demand from
membrane precursors. AEA is synthesized from N-
acylphosphatidylethanolamine (NAPE) by a specific
phospholipase D (NAPE-PLD). AEA is then broken down by
fatty acid amide hydrolase (FAAH) into arachidonic acid
(AA) and by cyclooxygenase-2 (COX2) into prostamines. 2-
AG is synthesized from diacylglycerol (DAG) by two sn-1–
specific diacylglycerol (DAG) lipases (DAGLα and
DAGLβ). Afterward, 2-AG is degraded by the serine lipase,
monoacylglycerol lipase (MAGL) into AA.
AEA is synthesized by a specific phospholipase D (NAPE-PLD) that hydrolyzes

N-acylphosphatidylethanolamine (NAPE) to AEA. NAPE-PLD is distinct from
other phospholipase D enzymes. Several redundant systems for the synthesis of
AEA have recently been discovered. Thus, PLD system is but one of several
mechanisms for the generation of this endocannabinoid (39).
Similarly to AEA, 2-AG is synthesized from membrane lipids. 2-AG has
higher selectivity and efficacy for CB1 and CB2 receptors than AEA, and the
regulatory process for 2-AG is different than for AEA. 2-AG is metabolized by
two sn-1–specific diacylglycerol (DAG) lipases (DAGLa and DAGLb) that have
been identified that can hydrolyze diacylglycerol (DAG) to 2-AG (5).
Degradative enzymes include fatty acid amide hydrolase (FAAH) as the enzyme
primarily responsible for AEA catabolism (5) and the serine lipase,
monoacylglycerol lipase (MAGL), responsible for 2-AG degradation (for
review, see Ref. (40)). AEA is taken up into cells via an AEA transporter that
also transports 2-AG into cells (39) and is thought to be the first step in the
termination of activity of both endocannabinoids. FAAH degrades intracellular
AEA (Fig. 15-1) and hydrolyzes 2-AG, but the reaction proceeds to completion
at least four times faster than with AEA. An alternative metabolic pathway for
AEA, which has been less studied, involves cyclooxygenase-2 (COX-2),
lipoxygenase (LO), and cytochrome P-450s and results in epoxides or
hydroxylated eicosanoids (41). A number of FAAH inhibitors have been
synthesized, and the structure–activity relationships for endocannabinoid
interactions with both the transporter and with FAAH have been reviewed (5).
FAAH-induced regulation of AEA may be the key regulator of AEA levels and,
thus, of AEA signaling pathways. In FAAH knockout mice, pain sensation is
significantly reduced, an effect correlated with increased AEA levels. Thus,
FAAH is a target for pharmaceutical interventions into the functions of the ECS
and its tonic control of pain perception (5,6).
2-AG is broken down by monoacylglycerol lipase (MAGL). A second
MAGL (5) is distributed in the CNS in the same brain regions as CB1 receptors
and, unlike FAAH, is a presynaptic enzyme, consistent with the role of 2-AG as
a retrograde signal (see next section).
ENDOCANNABINOID SIGNALING
The endocannabinoids bind both CB1 and CB2 receptors and produce effects on
transduction pathways similar to those of the exogenous cannabinoids (5). The
endocannabinoids are released postsynaptically to have “retrograde messenger”
presynaptic activity (Fig. 15-3). Thus, they travel backward compared to
classical neurotransmitters and regulate the release of neurotransmitters from the
presynaptic neuron. This retrograde diffusion of the endocannabinoids activates
presynaptic CB1 receptors, thereby altering presynaptic ion channel activity and
signal transduction. The process is initiated by depolarization of the postsynaptic
cell and results in decreased presynaptic neurotransmitter release. Cannabinoid
release commonly causes depolarization-induced suppression of inhibition
(DSI), which reduces inhibitory neural transmission. Depolarization-induced
suppression of excitation (DSE) can also occur, which is the suppression of
neuronal excitatory transmission. Long-term inhibition of neurotransmitter
release may also occur. The net effect of the ECS is to function as a regulator or
“rheostatic” mechanism on neuronal excitability (5,32,37).
Figure 15-3 Endocannabinoid retrograde signaling.
Endocannabinoids modulate synaptic signaling by traveling
in a retrograde manner across the synapse, following
postsynaptic neuron activation. This process begins when an
action potential traveling down the presynaptic neuron causes
the release of a classical neurotransmitter. After this
transmitter crosses the synaptic cleft and binds to a
postsynaptic receptor, postsynaptic neuronal activation causes
the “on-demand” synthesis and release of the
endocannabinoids, AEA and 2-AG. These endocannabinoids
travel back to the presynaptic neuron and bind to cannabinoid
type 1 (CB1) receptors, resulting in a retrograde signal that
attenuates presynaptic neuronal excitability.
Some of the endocannabinoid effects may not be mediated by CB1/CB2

receptors, including AEA-induced antinociception in CB1 knockout mice and the
inability to block the effects of AEA and certain other endocannabinoids by the
CB1 receptor antagonist rimonabant (5).
The wide array of effects produced by cannabinoids, including effects that
appear CB receptor independent, suggest the existence of novel cannabinoid-like
receptors such as GPR55 and GPR119 (for reviews, see (38,40)). Given the
plethora of effects of the cannabinoids and endocannabinoids, it is likely that
such effects are mediated by more than two receptors. The mechanisms
associated with these and other novel receptors will provide researchers with
multiple preclinical targets for potential clinical therapies.
Cannabinoid Pharmacokinetics
Inhalation (smoke or vapor or aerosol) produces the most rapid onset and intense
“high” (6). Marijuana and hashish may also be taken orally via food products.
However, the kinetics of oral absorption leads to a slower onset of the
psychoactive effects (about an hour) and a slower offset of action. The “high” is
of lesser intensity but longer in duration. The pharmacokinetics of THC and its
metabolism have been reviewed (42). THC is metabolized to the active
metabolite 11-OH-THC, which is unlikely to contribute significantly to THC’s
pharmacological effects because it is rapidly converted to conjugated 11-nor-9-
carboxy-THC (THCCOOH), which is inactive but serves as the primary urinary
marker for detecting cannabis use. THC accumulates in fatty tissues for long
periods of time after use. However, there is no evidence that THC exerts a
deleterious effect when slowly released from fat tissues (42). The relationship
between blood levels of THC and pharmacological effects is not initially linear.
A slight delay between the rapid appearance in plasma of THC and the onset of
behavioral effects makes the impairment produced by THC difficult to predict
based solely on plasma concentrations. Once THC is distributed completely to
all body compartments, the behavioral effects of THC are proportional to its
plasma concentrations (42). Lack of correlation of blood concentrations and
pharmacological effects is a confounder to the interpretation of impairment
following THC use. Complex mathematical models allow for the estimation of
time elapsed since marijuana usage based upon THC/metabolite ratios, a topic of
importance in criminal and workplace cases in which liability is assessed based
on drug use. Human-controlled drug administration studies led to the
development and validation of two equations for predicting time since last use:
model I based upon THC concentration (for infrequent users) and model II based
upon the THCCOOH/THC ratio (for all users and oral administration). Both
models were found valid for forensic use with 95% confidence intervals of
detection (42). Oral administration is associated with a first-pass effect and
delayed onset of effects (43).
Most synthetic cannabinoids are of high potency and short duration of
action, with metabolites that are more toxic than the parent compound, making
their identification via urinary markers very difficult (44).
Cannabinoid Pharmacodynamics
Tolerance—Preclinical Studies
Tolerance develops to the pharmacological effects of cannabinoids in a variety of
animal species, including pigeons, rodents, dogs, monkeys, and rabbits (45).
Tolerance develops to antinociception, anticonvulsant activity and catalepsy,
depression of locomotor activity, hypothermia, hypotension, corticosteroid
release, ataxia in dogs, and schedule-controlled behavior. The precise
mechanism of tolerance is unknown. Most research focuses on receptor
mechanisms such as receptor inactivation or desensitization or decreased
receptor number (down-regulation). Tertiary signaling processes and plasticity of
other neurotransmitter/neuromodulatory systems may also play a role, such as
those described above for the endogenous opioid system. Desensitization can
involve a conformation change in the receptor, internalization of the receptor,
uncoupling of the receptor from G proteins, or a combination of such processes.
The process of down-regulation includes loss of receptors from the membrane,
as evidenced by a decrease in receptor number in binding assays and/or changes
in receptor mRNA and protein levels. There is little evidence that chronic
administration of cannabinoids alters their disposition or metabolism in the brain
or periphery (45), suggesting that tolerance is pharmacodynamic in nature, rather
than a consequence of altered pharmacokinetics.
During tolerance, CB1 receptors lose the ability to inhibit AC, either through
desensitization or switching to Gs protein stimulation. Receptor desensitization
occurs following repeated administration of THC for a minimum of 3 days in
rodent studies. Dose-dependent alterations in cannabinoid receptor number and
affinity in rat brain regions are detected by autoradiography, with decrease in
CB1 receptor mRNA in the caudate (45). Selective down-regulation of receptors
following chronic THC administration in rat occurs in striatum and nigrostriatal
and mesolimbic areas. Conversely, tolerance to THC in the vas deferens model
did not involve an alteration in the number of cannabinoid receptors (5,45). The
process of cannabinoid desensitization mimics that of the beta-adrenergic
receptor and involves several kinase phosphorylation steps and possibly the
constitutive activation of several of the kinases. Down-regulation of cannabinoid
receptors following tolerance to cannabinoids is still incompletely understood. It
is possible that, in distinct brain regions, receptor mRNA and protein levels are
altered and that these changes are undetected when measuring whole-brain
homogenates.
Tolerance—Human Studies
Studies in humans indicate the development of tolerance to both cognitive and
psychomotor effects of heavy use of cannabis (and the potential cross-tolerance
to alcohol) were reviewed by Ramaekers et al. (46). Tolerance to cannabis
smoking was highly task dependent in that not all cognitive tasks indicated
tolerance had developed. Tasks such as tracking objects and reaction time to
respond did not show tolerance. In addition, cross-tolerance to alcohol in
cannabis users was not observed indicating the coadministration of alcohol with
cannabis smoking may lead to enhanced impairment of motor skills. In an
extensive review of the literature on cognition from published literature from
2004 to 2015 in human users of cannabis and other cannabinoids, predominately
cannabidiol (CBD), (47) report that tolerance does not develop to psychomotor
impairment following chronic cannabis use. However, studies of psychomotor
impairment are not in agreement as to the degree of persistence of impairment
upon chronic cannabis use. Tolerance does not develop to the cognitive
impairments observed upon acute cannabis use in most measures of cognition.
Cognitive impairments that do not exhibit tolerance include attention, learning
and memory, executive function such as planning, and tasks involving recall.
Numerous studies of cognition are reviewed (47) and indicate a lack of tolerance
to most cognitive tasks. In the case of attention deficits, abstinence from
cannabis did not attenuate the attention deficits. Residual deficits were observed,
although somewhat decreased with the elimination of the cannabinoids from the
body. In addition, in a small study, tolerance has been shown to the acute
intoxicating, but not the cardiovascular effects of orally ingestion of THC (48).
The mechanisms underlying tolerance in humans have not been determined, but
appear to include pharmacodynamic changes in CB1 receptors. Positron
emission tomography (PET) scans have been performed on chronic cannabis
smokers in order to measure changes in CB1 receptors versus those of
nonsmoking, healthy controls (49). PET scans indicate that chronic cannabis
smokers had regional decreases in brain CB1 receptors that were reduced by
~12% from controls. Such changes may indicate that the neurons in humans
show similar down-regulation of cannabinoid receptors following chronic use, as
do the studies in animals discussed above under preclinical effects. The
significance of such changes and correlation to the behavioral deficits upon
chronic cannabis use are unclear.
Physical Dependence/Withdrawal—Preclinical Studies

Preclinical studies indicate that animals develop physical dependence to the
effects of THC on repeated exposure (50). In animal studies, cannabis is self-
administered and acts via the same brain reward circuitry, as do other addictive
substances. Although it is difficult to establish self-administration paradigms for
THC (51), rats readily self-administer the THC analog WIN55,212-2. Self-
administration in rhesus monkeys is followed by withdrawal signs upon
cessation of the drug, indicating that DSM-IV cannabis dependence can be
produced in monkeys. Self-administration of THC and WIN55,212-2 is
abolished by administration of the CB1 antagonist rimonabant (51). Thus, the
unhealthy use and addiction potential of THC appears to be mediated by CB1
receptor activation. Several studies link withdrawal from THC with the opioid
system. The opioid/endogenous opioid system may play a modulatory role in the
severity of THC withdrawal signs (52). THC withdrawal is lessened in MOR
knockout mice and proenkephalin knockout mice (52). The relationship between
these animal models and human cannabis withdrawal remains unclear.
Cannabis Withdrawal—Human Studies
A cannabis withdrawal or abstinence syndrome is observed in human
experimental studies (21,53,54) and includes effects that are typically the
opposite of those produced by the drug, such as insomnia, anorexia, anxiety,
irritability, depression, and tremor. The characteristics of cannabis withdrawal
are those of a true drug withdrawal syndrome, although the predominant
symptoms are behavioral and affective, rather than physical. The amount of
cannabis consumed and the duration of use are critical components of the
intensity and duration of the withdrawal syndrome (55). In placebo-controlled
studies, oral THC administration decreases many abstinence-associated
symptoms and craving for cannabis (56). Human chronic heavy cannabis users
develop tolerance to its subjective and cardiovascular effects and experience
withdrawal symptoms on the abrupt cessation of cannabis use. The cannabis
withdrawal syndrome is comparable to that of tobacco in severity, with
simultaneous cessation of both substances more severe than either substance
alone. Withdrawal symptoms can serve as a negative reinforcement for further
use, with relapse rates following cannabis withdrawal higher than for many other
addictive drugs (55). Several recent studies have utilized PET scans in human
volunteers to image the CB1 receptor following chronic use and during
abstinence. Using a highly selective radioligand for the CB1 receptor such
as[18F]FMPEP-d2, which has a low nonspecific binding signal in spite of its
highly lipophilic characteristics, allows for reliable quantification of the CB1
receptors in the human brain. Hirvonen (57) evaluated volunteers consisting of
30 males who smoked ~10 cannabis cigarettes per day. Compared to 28 non–
cannabis-smoking male volunteers, the use of cannabis chronically decreases the
CB1 receptors by 20% in largely limbic (cortical) regions, with little effect in
subcortical regions. Thus, the effects of chronic cannabis use were highly region
specific. In addition, the effects of cannabis smoking on CB1 receptors were
dependent on the length of use and dose, with those using cannabis for a longer
duration of time having the greatest decrease in CB1 receptors. After 4 weeks of
abstinence, the CB1 receptors in the cannabis users did not differ significantly in
number to the normal volunteers. D’Souza et al. (58) using a slightly different
PET ligand evaluated the time course for the loss of CB1 receptors after cannabis
use in male volunteers with DSM-IV cannabis dependence versus nonsmoking
healthy control subjects and the time course for changes in CB1 receptor density
after short (2-day)- and longer-term (28-day) abstinence. In addition, people who
smoked tobacco were ruled out as subjects. People who used cannabis had
significantly less CB1 receptor density in region-specific brain areas not
including the thalamus and cerebellum. By 2 days of abstinence, there were no
differences in CB1 receptors in the cannabis-dependent group versus the healthy
non–cannabis-smoking volunteers. The volunteers reported cannabis withdrawal
signs that increased as the number of CB1 receptors decreased. Ceccarini et al.
(59) using both males and females who used cannabis observed region-specific
decreases in CB1 receptors in cannabis users using PET scans versus the normal
controls. There were no significant changes in CB1 receptor density in those
using cannabis from an early age versus those using for a shorter duration. But,
all changes indicated that use of cannabis decreased CB1 receptor density versus
the non–cannabis-smoking controls. Taken together, the PET studies indicate
that chronic cannabis use results in region-specific decreases in CB1 receptor
density, an effect that is rapidly reversed upon cessation of cannabis smoking
(abstinence) and the signs of cannabis withdrawal. A comprehensive review (60)
of studies of potential treatments for cannabis withdrawal indicated that no
current treatments conclusively have positive effects for the treatment of
cannabis withdrawal. The only potentially useful medication indicated in the
seven human studies reviewed (60) is gabapentin for which the results are
unclear as to the degree of efficacy.
Synthetic Cannabinoids—Preclinical Studies

Synthetic cannabinoids produce profound analgesia, associated with tolerance
development and physical dependence, and the effects can be “reinstated” or
observed again following a period of abstinence (9) indicating addiction
potential for the drugs. In most cases, but not all, the synthetic cannabinoids
produce similar effects in animals to those produced by administration of THC.
However, the effects observed were most often associated with a higher affinity
for either CB1 or CB2 receptors or off-site targets. In addition, the synthetic
cannabinoids produced effects not usually associated with THC in animal
studies, such as seizures.
Toxicity and Adverse Effects/Plant-Derived

Cannabinoids and Endocannabinoids
Cannabinoids and the ECS have both beneficial and adverse effects on virtually
every organ, and use of cannabinoids as therapeutic agents must be assessed
based upon the benefit/risk ratio for each system. Those with preexisting
diseases of the cardiovascular, liver, pancreas, and lung are particularly
susceptible to the adverse effects of cannabis smoking and the less well-known
effects of the numerous synthetic cannabinoids (22,61). Several of the organs
impacted by the use of cannabis are discussed below.
Psychomotor Effects
Cannabis dose-dependently impairs a variety of psychomotor functions in
humans, including object distance and shape discrimination, reaction time,
information processing, perceptual motor coordination, motor performance,
signal detection, tracking behavior, and slowed time perception (62). The effects
are generally larger, more consistent, and of increased persistence in difficult
tasks that involve sustained attention (63). There is an additive effect of cannabis
and alcohol on complex psychomotor tasks such as driving. Cannabis alone
produces minor impairment of driving performance, in part, because drivers are
aware of cannabis effects and drive cautiously to compensate. Cannabis smoking
disrupts eye-tracking performance, but the residual effects of a single cannabis
cigarette on eye-tracking performance are minimal 24 hours later (62).
Behavioral Effects
Although cannabis use has been suggested to cause an “amotivational
syndrome.” in humans, there is little rigorous scientific evidence to support its
existence (see (64,65)). Most studies have been narrow in scope and with small
sample sizes. An increased risk of quitting high school and increased job
turnover in young adults have been shown, but such studies fail to account for
the initial aspirations and goal orientation of the study participants. More
rigorous longitudinal studies with appropriate controls for baseline status find
residual cognitive impairment beyond the acute intoxication period in current
heavy users (15 joints/week), but similar deficits are no longer apparent 3
months after cessation of regular use, even among former heavy-using young
adults (65). A recent study (64) utilized 505 college students, quantified
numerous potential confounding risk factors such as other drug use, personality
traits, and general “self-efficacy” such as persistence. In a large statistical
evaluation accounting for the additional risk factors listed, only the use of
cannabis versus tobacco or alcohol was described by the authors as “prompting
lower initiative and persistence.” This study was the first to show that cannabis
use decreased factors associated with an increased amotivational syndrome
ascribed to cannabis use. Conversely, the authors did not find a correlation
between amotivational subjects and increased propensity to consume cannabis.
Many confounds are associated with such studies (66). There are marked
patterns of individual variability of substance use (eg, duration, frequency,
dosage, type), and, with the exception of a few studies, most researchers cannot
definitively isolate the effects of a specific drug due to a history of polysubstance
use. It remains to be seen if concurrent use of different substances (eg, cannabis
and alcohol) potentiates the long-term adverse effects of each drug.
Cognitive Effects
Recent evidence in animals indicates that the ECS is a selective and rapid
modulator of hippocampal synaptic function via effects on neurotransmitter
release (67). CB1 receptors in the hippocampus are a crucial element of this
influence. In general, exogenous administration of cannabinoids inhibits
neurotransmitter release in the hippocampus. Enhanced memory duration in
rimonabant-treated mice and CB1 knockout mice is consistent with the notion
that endocannabinoids are tonically active to dampen memory. However,
whether endocannabinoids such as anandamide and 2-AG tonically modulate the
neural pathways that underlie cognition remains unclear. Central CB1 receptor–
mediated signaling is involved in the facilitation of behavioral adaptation after
the acquisition of aversive memories. The cannabinoid analog WIN55,212-2, as
well as THC and AEA, blocks the formation of new synapses in rat hippocampal
cells in culture (67). The changes in the plasticity of the hippocampal system
may explain the memory deficits observed in THC users. Several human
psychiatric disorders such as generalized anxiety disorder and posttraumatic
stress disorder (PTSD) appear to involve failure to “forget” aversive memories.
Thus, modulation of the ECS might be a valuable therapeutic target for the
treatment of these disorders.
Cannabis use in humans is associated with subtle decreases in cognition and
memory via alterations in memory, attention, and integration of complex
information. Acute cognitive impairments following the use of cannabis include
loss of concentration and short-term memory and goal-directed activities (68).
Other reported effects of THC include disturbances of fine motor control and
coordination and problems in visual perception. Complex reaction time,
perception, reading, arithmetic performance, recall, and memory were affected in
all studies. THC may have more pronounced effects on cognition if a person is
using other drugs simultaneously. The effects of cannabis on cognitive behavior
are increased profoundly in a synergistic manner with concurrent use of MDMA
(“ecstasy”) (69). Given the polypharmacy that accompanies much cannabis use,
it is possible that other recreational drugs would have a similar deleterious effect
on cognition in combination with cannabis.
People who use cannabis show persistent deficits in specific cognitive
functions beyond the period of acute intoxication (see above discussion of
tolerance to cannabinoids in humans). Neurobiological studies indicate
involvement of the endogenous cannabinoid system after repeated exposure to
cannabis (70) and in the pathology of aging processes leading to dementia and
other associated brain disorders (71). In humans, all stages of memory, including
encoding, consolidation, and retrieval, are altered. Long-term potentiation, long-
term depression, and inhibition of the release of GABA, glutamate,
acetylcholine, and dopamine lead to amnestic effects of cannabinoids. Other
functions altered are time and space perception and sense of self
(“depersonalization”). In a 20-year prospective neurocognitive study,
noncannabis users, and persistent users, were assessed multiple times from ages
18 to 38 (72). Persistent users and those with pre-DSM 5 defined cannabis
dependence had relevant cognitive losses in learning, memory, and executive
decision-making even when controlling for initial IQ and final educational
levels, although the contribution of a change in IQ may play a lesser role than
socioeconomic status. Heavy cannabis use (subjects smoked marijuana on a
median of 29 days in the last 30 days and had cannabis-positive urine) is
associated with residual effects on memory and learning, implicating even short-
term heavy use with persistent neuronal changes into midlife (72). The longer
that cannabis is used, the more pronounced is the cognitive impairment. In
human PET studies, acute administration of THC increases activation in frontal
and paralimbic brain regions and the cerebellum, consistent with the behavioral
effects of THC (73). There is only equivocal evidence that chronic cannabis use
causes structural brain changes. Functional magnetic resonance imaging studies
in people who use cannabis chronically indicate neuroadaptations of brain
networks responsible for higher cognitive functions, which may not be reversible
with abstinence. A recent extensive review of longitudinal, some prospective,
neurocognitive studies in adolescence and adulthood concludes that the effects
of cannabis on memory are clearly dose-related as well as age-dependent as to
the onset of use (74). There are multiple types of memory and likely numerous
underlying mechanisms for any impairment of memory function. Thus, the types
of memory measured confound the observed effects of cannabis use on memory
function. Acute administration of cannabis in several studies results in
impairment of memory including short-term working memory, spatial memory,
and executive function among others. In most of the studies reviewed, no
persistent deficits were noted following cessation of cannabis use after a single
use. However, the quantitation of effects of chronic cannabis use and CUD on
memory is much more difficult to statistically determine. The measure of effects
of chronic cannabis use and those with CUD from numerous studies is also
reviewed (74). The results are confounded by the length of use, period/s of
abstinence prior to the study, and the type and THC content of the cannabis used
and age prior to first use. The majority of the studies reviewed indicate that long-
term use of cannabis and early onset of heavy cannabis use lead to persistent
impairment in some types of memory. However, interpretation of the results
from chronic cannabis users on persistent changes in memory function is
complex in that several additional studies show no persistent effects on memory.
Less persistent effects on memory were observed when the cannabis use was of a
product that contained a higher concentration of CBD than THC. The
importance of such differences in CBD/THC ratios on the residual effects of
cannabis on memory and neurocognitive deficits is yet to be determined
conclusively (70). A more recent prospective longitudinal study by Meier et al.
(72) assessed multiple dimensions of neurocognitive functions repeatedly in a
cohort of over 1000 children for up to 25 years. All children were assessed prior
to using cannabis. The persistent cannabis use group had a decline in overall
intellectual functioning compared to the non–marijuana use group. Four domains
were most impaired: working memory, perceptual reasoning, verbal
comprehension, and processing speed. Even after controlling for persistent
alcohol use, DSM-IV tobacco dependence, cannabis use in the last 24 hours or
last 7 days, and presence/absence of schizophrenia, the cognitive losses
remained significant. Use of cannabis in adolescence was highly predictive of
later cannabis dependence; onset of use in adulthood was not predictive of
cannabis dependence. A similar study by Stiles et al. (75) reports the results of
the study of either alcohol or cannabis use in participants from age 13 to 25.
Sampling was performed at regular intervals to determine frequency of cannabis
use and quantity of cannabis use throughout that age range. Statistical outcome
measures used were the completion of high school, higher education enrollment,
and higher education completion up to age 25. The results of the study indicated
that adolescents using cannabis weekly had a nearly twofold decrease in
completion of high school and enrollment in and completion of higher education.
Of interest to treatment programs was the effect of chronic alcohol use was less
statistically correlated with such decrements in educational outcome.
Psychopathology
Given the adverse psychiatric effects of the cannabinoid CB1 receptor
antagonist/inverse agonist rimonabant in clinical trials for obesity, which
included a greater than twofold increase in depression, and the discontinuation of
use by the subjects due to anxiety, in addition to perceived suicidal risks (76,77),
there has been increased interest in the role of the cannabinoid receptor and the
use of cannabis in mental illness. Numerous large, prospective, longitudinal
studies suggest that use of cannabis increases the risk for schizophrenia, worsens
symptoms, and is associated with a poorer prognosis, effects related to the dose
of drug and other risk factors (76). In addition, persons with genetic vulnerability
to psychoses or a previous psychotic episode, as well as those who initiate
cannabis use in early adolescence, are particularly prone to the development of
schizophrenia (76). The causal relationship between cannabis use and
schizophrenia is unclear. Given the number of environmental factors that are
likely interacting with genetic factors in the development of the disease,
cannabis appears to be a risk factor. The use of cannabis increases the risk of
nonaffective psychotic illness three- to sixfold (78,79). The association between
cannabis use and depression is less significant after correction for confounds
such as polydrug use (80,81). The association between cannabis use and
depression or other affective disorders or suicidality remains unclear. Some
reviews find cannabis use associated with “amotivational symptoms,” while
others find no such symptoms, but do report significant effects on general health
and well-being that might account for observed motivational effects (64).
In preclinical models of neurological disorders, the ECS is altered (82,83),
with significant change in the synthesis and degradation of endocannabinoids
upon chronic administration of THC to rodents. Such changes suggest that
chronic THC exposure may alter neuronal plasticity in ways with therapeutic
potential in numerous disease states.
Effects on Major Organ Systems

Respiratory
The major adverse health effect associated with cannabis smoking is damage to
the respiratory system. Many of the same mutagens and carcinogens in nicotine
cigarette tobacco smoke are found in cannabis smoke. However, clinical and
epidemiological evidence linking cannabis smoking to chronic obstructive
pulmonary disease or respiratory cancer has not been shown. A recent study
using data from the National Health and Nutrition Examination Survey of over
7700 individuals details a self-report from participants from 18 to 59 years of
age as to cannabis use and combined such self-reports with measures of lung
function. In this large and statistically detailed report, the duration of use, use of
tobacco, history of significant respiratory diseases, as well as the sex and race of
the subjects were examined as covariates among numerous other factors detailed
in the publication (84). Increased respiratory illnesses trended toward and
increase concurrently with increased numbers of days per month of cannabis
smoking and support the results of numerous reports (reviewed in the paper) of
airway inflammation, decreased airway conductance, and airway edema. The
study did not indicate that chronic cannabis smoking led to small airway disease
or airflow obstruction and thus no effects on lung function. In addition, the
International Agency for Research on Cancer found the epidemiological data
inconclusive as to the increased risk of cancer from cannabis use versus that of
tobacco smokers (85).
Immunological
The CB2 receptor is expressed on cells of the immune system, bone, and in the
CNS, leading to the hypothesis that the cannabinoid system plays a significant
role not only in immune modulation but also in numerous additional
pathological states. In preclinical tests, the effects of CB2 receptor activation
extend beyond the initial effects on the macrophage to include effects on most
modulatory systems involved in neuropathic pain and autoimmune disorders
(6,86). The role of both agonists and antagonists of the CB2 receptor is likely to
become one of the major new therapeutic “fronts” for drug development,
especially because CB2 agonists do not have the psychoactive effects associated
with CB1 receptor agonists such as THC. Immunomodulatory effects of THC on
macrophage function are abolished in CB2 knockout mice devoid of CB2
receptors (5), which are critical for gene regulation of immune cells, possibly via
decreased production of various chemokines such as interleukin-I (IL-I), leading
to immune suppression.
Immune suppression by THC protects pancreatic beta cells in an
experimental model of autoimmune diabetes. These findings contrast with other
data indicating a potential stimulation of immune responses via lymphocyte
activation (87). Thus, cannabinoid use to decrease inflammation could be
accompanied by an increase in viral infections. Overall, it appears that THC
decreases macrophage function and natural killer cell activity. THC increases
HIV-1 host infection in cell lines. Thus, the effects of cannabinoid or
endocannabinoid activation of the immune system are complex, but numerous
studies are in agreement that host resistance is impaired by THC administration.
The increase in mortality following THC administration to animals is highly
dependent upon the infectious agent (88).
Cardiovascular
In humans, cannabis increases heart rate and produces orthostatic hypotension,
which is blocked by rimonabant. Direct stimulation of the cardiac pacemaker by
cannabis increases heart rate, making the drug less safe in cardiac patients. In
healthy young users, these cardiovascular effects are unlikely to be of clinical
significance. However, cannabis smoking has been shown to be associated with
coronary artery disease in both older and young, healthy subjects (89). Synthetic
cannabinoid use has been linked to cardiovascular damage and myocardial
infarction in previously healthy young people (48). Preclinically, both CB1 and
CB2 receptors have been implicated in a number of cardiovascular processes,
including vasodilation, modulation of the baroreceptor reflex in the control of
systolic blood pressure, inhibition of endothelial inflammation, and progression
of atherosclerosis, making cannabinoid drugs potential targets for therapeutic use
in a number of cardiovascular diseases (90). Endocannabinoids regulate platelet
function and possibly promote thrombogenesis (91) and may also influence
hematopoiesis, which can worsen congestive heart failure and increase
hypertension. The ECS is implicated in the mechanism of hypotension
associated with hemorrhagic, endotoxic, and cardiogenic shock.
Endocannabinoids have a protective role in myocardial ischemia (83,90). Recent
studies indicate the existence of a novel endothelial and cardiac receptor that
mediates certain endocannabinoid-induced cardiovascular effects. Furthermore,
cannabinoids have been considered as novel antihypertensive agents (83). THC
and its analogs have profound hypotensive and bradycardic effects in rats, which
are mediated by the CB1 receptor (83). The critical role of endocannabinoids in
such pathophysiological states suggests important therapeutic targets for
conditions such as endotoxic and hemorrhagic shock.
Liver
Cannabinoid receptors play a crucial role in the pathogenesis of a variety of liver
diseases in humans (92). Daily cannabis use is a predictor of fibrosis progression
via a steatogenic effect. Thus, daily cannabis use in patients with liver disease
can have deleterious effects. The predominant liver effects of cannabis (THC,
cannabidiol) in healthy human cannabis users are inhibition of liver microsomes,
resulting in cannabis-induced prolongation of the action of barbiturates.
Cannabis users metabolize and activate or inactivate drugs more slowly than
normal (93). In preclinical studies, hashish induces carcinogen-metabolizing
enzymes, potentiating the deleterious effects of N-nitrosamines and aromatic
hydrocarbons, for example, benzo(a)pyrene in the liver (93). In mice, activation
of CB1 receptors contributes to alcohol-induced steatosis, an increase in liver
fibrous tissue.
Kidney
Renal complications are rare following cannabis use, with only one case of renal
infarction documented (94). An additional case of nephropathy associated with
marijuana smoking was recently reported (95). Synthetic cannabinoid use has
been linked to acute kidney failure due to acute tubular necrosis. The mechanism
for such damage is not known, but several potential causes are reviewed by Alp
et al. (96). Although this condition is increasing as the use of synthetic
cannabinoids increases, the condition is often not diagnosed and may present as
psychiatric symptoms secondary to the electrolyte changes produced.
Endocrine
Preclinically, THC alters pituitary hormones (97). Virtually no hormonal system
remains unaffected by activation of cannabinoid receptors, although the effects
are more often observed in preclinical than clinical studies. Effects of
cannabinoids include inhibition of pituitary luteinizing hormone, prolactin
(PRL), and growth hormone (GH), with little effect on secretion of follicle-
stimulating hormone. Cannabinoids inhibit GH secretion due to stimulation of
somatostatin release (97). Mice lacking the CB1 receptor have lower bone
density than their wild-type controls, leading to the hypothesis that cannabinoid
agonists may improve bone density (83). The synthetic cannabinoid analog
WIN55,212-2 modulates pituitary hormones via the CB1 receptor, particularly in
the anterior lobe of the pituitary, site of release of GH and PRL (inhibited by
WIN55,212-2) in normal and hyperactive pituitary states (98). Cannabinoids
affect thyroid function via a reduction of iodine accumulation and reduction of
levels of thyroxine and thyroid-stimulating hormone in animals. There are no
data regarding the effect of cannabinoids on thyroid function in humans (97).
Basal and stress-induced plasma levels of adrenocorticotropin (ACTH) and
corticosterone are higher in CB1 receptor knockout mice versus wild-type
controls. Thus, CB1 receptor activation plays an important role in stress
responses, release of ACTH, and production of cortisol (99). THC-induced
increases in ACTH and corticosterone requires cannabinoid and opioid
receptors. It is hypothesized that human neuropsychiatric disorders, including
anxiety and PTSDs, involve abnormal responses to stress, an effect likely due to
altered activation of the ACTH/cortisol pathway. Activation of the CB1 receptor
by endocannabinoids in rodent models modulates responses to acute, repeated,
and variable stress, an effect enhanced by prior stress of the animals. Thus,
modulation of the hypothalamic–pituitary–adrenal axis via cannabinoids may
have therapeutic potential in such disease states (100). Of considerable concern
is the preclinical and clinical evidence that the cannabinoids and ECS are
contributors to the multifactorial effects underlying the development of diabetes
including insulin release and severe cardiovascular and neuropathic etiologies
that accompany the disease. The use of THC is considered a risk in diabetic
patients (101).
Reproduction and Pregnancy

Human fertility is partially regulated by the ECS (CB1 receptor, CB2 receptor,
FAAH, and NAPE-PLD levels and localization change throughout the menstrual
cycle). Both male and female cannabis users show decreased fertility. In some
studies, females show reduced pregnancy success, including early pregnancy
termination, fetal abnormalities, and embryotoxicity (102). Males have
decreased plasma testosterone and reduced sperm motility and counts (103).
Cannabis use reduces the success of in vitro fertilization (IVF) and IVF
outcomes for both males and females (104). Murine studies indicate that the
ECS plays a role in the development and implantation of the embryo by
synchronizing the developmental stage of the embryo to the receptive stage of
the uterus (27). In animal models, maternal cannabinoid consumption alters the
neurological development of neurotransmission systems, particularly those
involving serotonin, dopamine, and GABA (105), and can cause lifelong
changes in behavior, including hyperactivity, learning deficits, and enhanced
response to rewarding drugs (106).
In 2015, >10% of pregnant women reported using marijuana in the past year,
and about 5% of pregnant women report use within the past month. The lipid
solubility of THC allows for its rapid transfer to the fetus through the placenta as
well as rapid transfer into breast milk (75). Human prospective longitudinal
studies have unveiled numerous potential complications from prenatal cannabis
exposure (PCS) (107,108). In humans, some studies link PCS to preterm labor,
decreased birth weight, increased stillbirths, and increased admissions to
neonatal intensive care units (NICUs), while others do not observe these effects.
Studies on children who had PCS are also variable, but often show impairments
in mental development, including decreased memory, verbal reasoning, and
attention and sleep efficiency and an increase in impulsivity and hyperactivity
(78,108). PCS complications may carry into adulthood; functional magnetic
resonance imaging (fMRI) scans show decreased activity in parts of the
prefrontal cortex and the cerebellum and increased activity in frontal gyrus
(109). PCS adults potentially have decreased scores in learning, memory, and
visual and abstract reasoning and had higher rates of depression, impulsivity,
hyperactivity, and delinquency (78,108). Murine studies have shown that the
ECS is critical during neurodevelopment and alterations in this system affect
cortical circuitry development, which is consistent with the toxicities seen in
human studies. Furthermore, mouse studies have shown that PCS results in adult
offspring with altered emotionality, cognitive defects, changed locomotor
activity, and increased susceptibility to substance use disorders, which is also
similar to the preliminary human results (105).
Some studies examining cannabis use and pregnancy did not reveal any
negative impacts (110), indicating a need for further research. However, the
many molecular animal studies, preliminary human data, and the high cannabis
use rates during pregnancy indicate a need for caution; women should be
informed of the potential risks of marijuana use during pregnancy.
Intoxication and Overdose

Marijuana users frequently report euphoria, hunger, and relaxation and less often
panic, anxiety, nausea, and dizziness. In rare instances, marijuana can increase
paranoia and panic attacks at oral doses of 20 mg or higher (82). These more
severe effects are most often reported by naive users or patients receiving THC
therapeutically who are unfamiliar with the drug’s effects. Discussion of
potential effects reduces the intensity of such experiences; experienced users
rarely report these effects (65,82).
Overdose from ingested cannabis preparations is on the rise due to increase
in availability. The major effects observed are sedation and confusion,
tachycardia, chest pain, and hypotension with the potential for severe respiratory
depression (111). The groups most commonly admitted for treatment are those
<5 years old and those in the 15- to 19-year-old group. The majority of the
patients were treated in an outpatient setting. Studies of overdose and emergency
room visits following cannabis use have been conducted in Europe using large
numbers of emergency reports (112). Overall, 18%-37% of all drug-related
emergency room visits are for overdose with cannabis resulting in anxiety,
confusion, and depression. Sudden cardiac death has been reported in a small
number of patients usually when ingested in combination with other drugs
especially alcohol and in those patients with cardiac risk factors. A recent large
retrospective analysis of cardiovascular risk following the use of cannabis and
cannabinoids (113) found that cannabis/cannabinoid use poses a “significant
cardiovascular impact,” especially when used in large doses and in overdose
situations. The greatest impact was on cerebral blood flow and the development
of ischemic strokes. The authors stress that more research needs to be performed
to determine the cause of such effects of the cannabinoids.
NONCLINICAL USE
Relative Addiction Liability

Cannabis Use Disorder (CUD)/Substance Use Disorder
Both the DSM-5 and the World Health Organization’s International
Classification of Diseases recognize cannabis use disorder (21). CUD may
include the development of tolerance to cannabis and withdrawal signs upon
cessation (21). Clinical and epidemiological evidence indicates that CUD occurs
in people who use cannabis in heavy, chronic amounts, as exhibited by a lack of
control over their cannabis use and continued use despite adverse personal
consequences (for reviews of CUD and the studies of potential treatments, see
Refs. (21,60,79,114,115)). In 2012, among Americans who reported using
cannabis at least once, over 13% reported criteria supporting pre-DSM5
cannabis abuse or dependence (115). Treatments for CUD are in the
developmental stage with several cannabinoids, as well as noncannabinoids
showing promise as therapies. Difficulties in development of treatments for
CUD come from the underlying complexity of the potential interactions of
cannabinoids with other neuronal receptors/substrates in the development of
CUD. Although risk factors for CUD and relative addiction liability are being
extensively studied, causal factors underlying the disorder remain unknown.
Several longitudinal studies of the risk for developing CUD after initial and
short-term exposures and the long-term outcomes have been published and
include studies on sex differences in the development of CUD (114,116–118).
Females who use cannabis were more likely than males to develop such a
cannabis disorder. For reviews of CUD, see Refs. (21,119). The majority of the
chemical entities present in cannabis, as well as the pyrolysis (burning) products,
have not been evaluated for either psychoactive or toxicological properties.
Thus, the effects of prolonged drug use are difficult to predict, although
neurochemical changes are observed upon tolerance and physical dependence to
THC (see “Pharmacodynamics” section). Although the risk factors for the
development of CUD are not known, recent research has focused on genetic and
neurochemical changes in the brain as potential risks. A recent extensive review
in humans indicates that maternal exposure to cannabis is associated with
genetic and epigenetic changes that are inheritable and sex related (120).
Synthetic Cannabinoids—Adverse Effects

and Toxicity
With the regulation of synthetic cannabinoids as Schedule 1 drugs, numerous
nonscheduled analogs have been developed. All such synthetic cannabinoids are
derivatives of drugs designed for preclinical studies, not for human use, and have
preclinical effects including increased cannabinoid receptor affinity and off-site
receptor targets that differ from THC (121–123). The adverse effects of the
synthetic cannabinoids are varied, often differ from that of cannabis, and are
often more severe and longer-acting (9,10,91), Such differences are due to the
plethora of novel structures of the synthetic cannabinoids and the differences of
such structures in pharmacokinetics/pharmacodynamics in the body. In addition,
the synthetic drugs are often combined with other drugs such as caffeine, etc.
Effects include the potential for psychotic/manic episodes and cardiovascular
effects leading to cardiac arrest, stroke, and seizure induction (10). In addition,
the synthetic cannabinoids when used most frequently as daily will lead to
withdrawal signs upon cessation. The major adverse effects observed following
synthetic cannabinoid administration in case reports include acute kidney injury
and emesis along with a potential for butane explosion upon use due to improper
extraction of precursors of the synthetic drugs from cannabis (19,91). Case
reports of patients admitted to ED after acute use may not necessarily represent
typical use effects. ED case series (121) reported patients presenting with
aggression, paranoia, anxiety, agitation, visual hallucinations, and somnolence.
Medical problems included sinus tachycardia, systolic hypertension, and
elevated blood glucose. Two patients were treated with restraints and intravenous
lorazepam. Symptoms resolved in 3-6 hours. In a series of 41 individuals with
cannabis dependence applying for a treatment study (125), 50% had used
synthetic marijuana. Adverse events among people who used synthetic
marijuana on a regular basis included trouble thinking in 30%, headaches in
24%, and palpitations in 14%. Diaphoresis, panic attacks, cough, and fatigue
were also listed. A more ominous adverse effect of synthetic marijuana use
recently reported to the U.S. Center for Disease Control and Prevention is acute
renal damage (124). Six states reported renal impairment after synthetic
marijuana smoking. Serum creatinine levels ranged from 6 to 21 mg/dL (normal
0.6-1.2 mg/dL). All patients required hospitalization; five patients required
hemodialysis. The mechanism of renal damage was not reported. Mills (125)
states “Between April 1, 2015 and May 31, 2015 there were a total of 1243 ED
visits due to synthetic cannabinoids in Mississippi and 17 deaths. This means
that over a 2-month period, more people died in Mississippi from synthetic
cannabinoid use than had reportedly died around the globe from 2004 to
December 2014.”(124). In addition, Law (126) has reviewed the data from the
Centers for Disease Control that report there was an increase of 330% in the first
6 months of 2016 in poison-related calls related to overdose of synthetic
cannabinoids. Most of those affected had cardiovascular effects including
tachycardia, as well as agitation and confusion. Of those calls, 0.5% were
documented to have died. The risk for overdose and toxicity with synthetic
cannabinoids is 30-fold higher than that for cannabis alone (127). The severity of
the adverse effects of the synthetic cannabinoids has only recently been
monitored (128) extensively with larger numbers of patients needing to be
evaluated to determine specific effects on diverse organ systems and the
potential for permanent impairments.
Clinical Uses
Therapeutic potential for cannabinoids is currently under investigation, including
nonpsychoactive cannabinoids such as cannabidiol and numerous
endocannabinoids and the modulators of their synthesis and degradation. The
number of potential uses for the drugs is diverse, including both the central and
peripheral sites of action from “brain to bone,” and was summarized extensively
previously by Pertwee (5). The most recent and very extensive review of the
effects of cannabis via many routes is presented in a monograph from the U.S.
National Academy of Medicine (129). The reader is encouraged to review the
clinical literature presented as to the correlations or lack thereof of cannabis use
and over 20 psychiatric and neurological illnesses and would serve the reader as
a very detailed adjunct to the material presented in this book chapter. The issue
of “cannabis as medicine,” also referred to by laypeople as “medical marijuana,”
is also covered in section 14 of this textbook. The problems associated with use
of cannabis have also been reviewed and generally lie in the plethora of effects
of drugs binding to the CB1 receptor, with psychoactivity and mood alterations
being those effects most studied. However, the development of modulators of the
ECSs provides an increasingly large number of potential therapeutic uses
(5,129), in large measure due to the identification of novel sites of action as
possible therapeutic targets. The use of mixed CB1/CB2 agonists that fail to cross
the blood–brain barrier is particularly useful in alleviation of peripheral
neuropathic pain in animal models, but has yet to be tested in humans. The
treatment of localized pain with transdermally administered cannabinoid
“patches” largely avoids the psychoactive effects produced by centrally CB1-
accessible cannabinoids in animal models. Development is also ongoing to
develop a selective CB2 receptor agonist (5,129). Studies of the CB2 receptor
have lagged behind study of the CB1 receptor. Potential sites for activity of CB2
agonists lie largely in the peripheral immune systems in the brain, lung, liver,
and cardiovascular system, making CB2 receptor modulators potential
therapeutic targets for diseases of such areas (5,129). As more definitive roles
for the CB2 receptor are determined, specific agonists will likely become critical
in the treatment of numerous disease states.
Controlled clinical trials indicate that smoked cannabis significantly
decreases neuropathic pain in HIV-positive individuals (6). Side effects were not
life threatening. Therapeutic uses for cannabis have been anecdotally reported
for thousands of years. Only recently have several uses described in folk
medicine been formally evaluated. The most intense interest has been directed
toward the prevention of weight loss in AIDS patients, management of pain,
prevention of emesis, control of glaucoma, and control of movement disorders.
The use of smoked cannabis remains both politically and scientifically
controversial, although studies of smoked cannabis are currently underway in the
United States. The availability of synthetic THC in capsule form provides a
potential alternative to the smoked plant material, as do a variety of novel
delivery systems including vaporizers. The development of alternative methods
of drug delivery using either pure THC or one of the newer THC derivatives
may obviate these problems. Increasing understanding of the role of the ECS in
the etiology of disease states, coupled with the pharmacological activity of
endocannabinoids administered exogenously, has opened a new and exciting
area for the development of potential therapeutic agents. The following
paragraphs describe some of the current clinical uses for the cannabinoids.
Antiemetic Effect
Two oral formulations described previously, dronabinol (synthetic THC)
(Marinol) and nabilone (synthetic THC analogue) (Cesamet), are approved by
the U.S. FDA to treat emesis refractory to conventional antiemetics, as well as
related cachexia. Cannabinoids are slightly more efficacious than conventional
antiemetics such as metoclopramide, phenothiazines, and haloperidol at doses of
5-10 mg every 4 hours for dronabinol and 1-2 mg twice per day for nabilone
(130). Side effects such as dizziness and dysphoria limit the use of such drugs.
There is some evidence that the combination of a dopamine antagonist and
cannabinoid is superior to either alone and is particularly effective in preventing
nausea.
Appetite Stimulation and Cachexia

Smoked cannabis has been shown to stimulate appetite (131). Clinical trials with
smoked cannabis indicate some improvement in appetite and slight increases in
caloric intake and weight gain. In AIDS patients with the lowest CD4+ counts,
dronabinol was not harmful; and long-term THC treatment up to 1 year was safe
for anorexia associated with weight loss in patients with AIDS. One placebo-
controlled, within-subjects study in individuals with HIV-induced cachexia
evaluated smoked marijuana and oral dronabinol (5 mg) across a range of
behaviors including eating (131). As compared with the placebo, both marijuana
and dronabinol dose-dependently increased daily caloric intake and body weight
in HIV-positive marijuana smokers. At the doses used, cannabis produced
significant intoxication, while dronabinol did not.
The appetite-stimulating effects of THC (mediated by CB1 receptor
activation) led to the development of the CB1 receptor antagonist SR141716A
(rimonabant) as an agent for weight reduction (132). By the end of 2007, the
drug was approved for marketing in more than 50 countries. With increasing
worldwide adverse mood events, rimonabant was withdrawn from the market in
late 2008. Clinical development of all CB1 antagonists was halted. However, the
effects of rimonabant on weight reduction expanded a new area of preclinical
research on the regulation of appetite and metabolic processes by the
cannabinoids and endocannabinoids.
Glaucoma
Most, but not all, studies reveal that smoking cannabis significantly lowers
intraocular pressure (133). The synthetic cannabinoid nabilone is marketed in
Europe for the treatment of glaucoma. However, evidence is lacking that
cannabis (or THC) is capable of lowering intraocular pressure sufficiently to
prevent optic nerve damage, is more effective than other agents, or is effective in
patients refractory to current therapies. The necessity of smoking cannabis or the
systemic administration of synthetic cannabinoids for beneficial effects also
tempers enthusiasm for their use in managing glaucoma. Development of a
cannabinoid derivative that is effective topically could be beneficial in that it
would most likely exert its effects through a mechanism distinct from that of
current medications. Topically applied endocannabinoids or their modulators and
cannabinoid ligands may be of significant benefit in the treatment of glaucoma.
The mechanisms responsible for the intraocular pressure–reducing effect of
cannabinoids are not understood, but are likely to involve direct effects on ciliary
processes such as vasodilation and decreased capillary pressure. Recent reviews
also mention the potential for endocannabinoid tone to play a therapeutic role in
the treatment of glaucoma (5,83).
Preclinical Studies—Ongoing
Appetite Stimulation and Control
From the time of birth, the ECS may be a factor in food intake (133). Newborn
mice given SR141716A fail to suckle, lose weight, and die if not rescued with
administration of THC or endocannabinoids such as 2-AG. Endocannabinoids
regulate energy balance and food intake in newborns and suckling behaviors by
acting at both central and peripheral sites. Central control appears to be via the
limbic system (site of the desire or “craving” for food), as well as the
hypothalamus and hindbrain. Peripheral intestinal control and endocannabinoid
effects on adipose tissue are additional players in the control of appetite. The
ECS interacts with a number of other molecules involved in appetite and weight
regulation, including leptin, ghrelin, and the melanocortins (133). CB1 receptor
knockout mice eat less than their wild-type littermates, and endocannabinoids in
the hypothalamus tonically activate CB1 receptors to maintain food intake. The
mechanism by which endocannabinoids regulate food intake includes
modulation of leptin, the major signaling peptide through which the
hypothalamus senses satiety. Defects in the leptin/endocannabinoid interplay
have been proposed to underlie obesity in genetically obese rats and may
underlie obesity in humans. Endocannabinoids increase leptin production from
adipocytes; CB1 receptor–deficient mice contain less circulating leptin than
wild-type mice. Conversely, ghrelin released during food deprivation signals the
hypothalamus of the need for energy intake. Ghrelin up-regulates hypothalamic
endocannabinoid levels. Thus, two key hormones controlling food intake, leptin
and ghrelin, are not only regulated by endocannabinoids but also regulate
endocannabinoid levels in seemingly opposing ways, an effect mediated by CB1
receptors. Data from both animal studies and clinical trials with rimonabant
indicate that these and other regulatory effects occur also in peripheral tissues,
particularly in adipocytes, and that the ECS may play an important role not only
in energy intake but also in lipid metabolism and accumulation. These new
insights into the role of endocannabinoids in eating provide novel therapeutic
possibilities for the treatment of a variety of eating disorders via the use of drugs
designed to alter peripheral, but not central, cannabinoid receptors.
Anticonvulsant Effects
Cannabis’ therapeutic potential as an anticonvulsant was shown in the 1940s
when children, poorly controlled on conventional anticonvulsant medication,
improved after the use of cannabis (134). Recent clinical trials of smoked
cannabis, oral cannabis extracts, cannabidiol, and oral cannabis in the treatment
of epilepsy of various etiologies are reviewed in detail by Friedman and
Devinsky (135). The authors conclude that there have been a paucity of
controlled trials using cannabinoids to treat epilepsy, but current clinical trials
with a 99% pure CBD drug show significant (54%) reduction in seizures in data
released preliminarily. Current proposed uses for CBD in the treatment of other
seizure disorders are also discussed based on the success shown in the current
clinical trials. Cannabidiol has moderate anticonvulsant activity in animals. In
animals, the CB1 receptor activated by exogenous or endogenous cannabinoids
produces an anticonvulsant effect, whereas status epilepticus in rats results in
persistent redistribution of brain CB1 receptors that results in altered coupling of
the receptor to G proteins (136). The role of the ECS in the regulation of
neuronal firing, action potential modulation, and excitotoxicity has led to
numerous studies of the role of CB1 receptors in epileptiform activity (136).
These findings indicate that the CB1 receptor plays a critical role in neuronal
firing and could be a therapeutic target for the treatment of epilepsy and other
diseases resulting in seizures, such as head trauma.
Neurological and Movement Disorders

There are numerous anecdotal reports that smoked cannabis relieves spasticity
arising from MS and spinal cord injury. However, there are few controlled
studies comparing the effectiveness of either cannabis or THC with other
therapies. The ECS is subject to plasticity changes of various durations in
pathological conditions such as neurological, neuropsychiatric, and movement
disorders. Endocannabinoid tone plays a critical role in the modulation of basal
ganglial mediation of the spasticity in Parkinson disease. The importance of such
changes is yet to be determined. Several clinical trials indicate that cannabinoids
ameliorate spasticity and pain and improve quality of sleep in MS patients
(129,137). Over 90% of MS patients report improvement after taking cannabis.
In animal models of demyelination, cannabinoid receptor agonists decrease
motor dysfunction in a manner similar to the effects in humans. (For an
extensive review of neurological disorders and the treatment with cannabis, see
(129).)
Analgesia
A variety of pharmacological, anatomical, and electrophysiological
investigations indicate that the CB1 receptor system plays a fundamental role in
regulating pain behavior (6,86). CB1 receptors are expressed at high levels in a
variety of peripheral and central neurons that participate in pain perception. CB1
agonists produce analgesia by acting at several sites along pathways for pain
transmission peripherally, spinally, and supraspinally. Endogenous ligands that
bind to cannabinoid receptors, such as the endocannabinoids, are targets of the
majority of studies of CB1 and CB2 receptors in the modulation of pain. In
addition, modulators of the synthesis, transport, and degradation of the
endocannabinoids have become increasingly important therapeutic targets and
are discussed in more detail in the “Neurobiology” section and detailed in Figure
15-3.
Anandamide and 2-AG produce antinociception when administered to
animals. The short half-lives of the endocannabinoids (5) present a significant
challenge in investigating their function. However, the identification of FAAH
(25) as the enzyme primarily responsible for AEA catabolism and the serine
lipase MAGL responsible for 2-AG degradation has provided valuable targets to
increase endogenous levels of each of these respective endocannabinoids, by
using genetically engineered mice devoid of FAAH as well as pharmacological
inhibitors of each of these enzymes. As expected, FAAH (−/−) mice have an
impaired ability to metabolize AEA, as well as noncannabinoid fatty acid
amides. Consequently, they possess highly elevated endogenous levels of these
compounds in the central nervous system (CNS) and periphery. FAAH (−/−) mice
display phenotypic hypoalgesia in the tail immersion, hot plate, and formalin
tests, which are completely normalized by rimonabant. FAAH (−/−) mice also
exhibit decreased inflammatory responses in the formalin and carrageenan paw
edema models (85).
Both irreversible (eg, URB-597) and reversible (eg, OL-135) inhibitors of
FAAH produce similar pharmacological effects as those observed in FAAH(−/−)
mice, including increased brain AEA levels, increased sensitivity to the
pharmacological effects of injected AEA, and a CB1-mediated decrease in pain
sensitivity in the tail immersion, hot plate, and formalin tests. Thus, FAAH
inhibitors such as URB-597, as well as MAGL inhibitors, produce
antinociception. In addition, the ECS is an active component of chronic pain, for
example, the CB1 antagonist rimonabant produces hyperalgesia in rats and mice
(41).
Pain can lead to functional adaptations within the ECS. For example, spinal
nerve ligation in the rat up-regulates CB1 receptors in the thalamus and spinal
cord. In an analogous study, AEA levels in the periaqueductal gray region (PAG)
were increased by an injection of formalin into a hind paw. Electrical stimulation
of the dorsal PAG releases AEA in this brain region and produces a CB1
receptor–mediated analgesia. Anandamide and, to a lesser degree, 2-AG are
metabolized by cyclooxygenase-2 (COX-2) and the lipoxygenase (LO)
enzymatic systems, generating a variety of prostamides and leukotriene
derivatives. The interactions of AEA and 2-AG with such enzymatic systems are
complex; the resultant effects of the metabolites remain an area for study in that
prostanoids such as prostaglandins have long been known as mediators of pain
(41).
There is increasing evidence that the CB2 receptor is a critical component of
inflammatory pain (86), in addition to having multiple effects on inflammation,
autoimmune responses, and bone density, all potential players in the etiology of
such pain. CB2 receptors were identified in brainstem neurons, which could be a
possible site of action (138). In addition, sciatic nerve section or spinal nerve
ligation causes an up-regulation of CB2 receptors in the dorsal horn of the spinal
cord (139). It is reasonable to speculate that the analgesic and anti-inflammatory
effects of CB2-selective agonists result from a combination of actions at both
neuronal and immune sites. A large number of CB2-selective analogs have been
developed that are effective in acute pain and inflammatory models at doses that
do not produce the behavioral effects ascribed to the CB1 receptor (86).
The use of THC as an adjunct to the opioids for pain control and prevention
of opioid tolerance and physical dependence is an area of increasing interest (5).
Cannabinoids are active as analgesic drugs when administered to laboratory
animals by several routes of administration (6). Early studies established that
oral THC is effective in the rat paw pressure test. Similarly, the synthetic
cannabinoid WIN55,212-2 alleviates the pain associated with sciatic nerve
constriction in rats and capsaicin-induced hyperalgesia in rats and in rhesus
monkeys. There is considerable evidence for interactions of the cannabinoids
with opioid systems in the modulation of nociception (140,141). CB1
cannabinoid and opioid receptors have similar anatomical distributions in the
dorsal horn of the spinal cord and in several brain structures associated with
nociceptive transmission. THC and morphine synergize the production of
antinociception in mice (142), in normal and arthritic rats (143), and in chronic
pain states (140). The functional coupling of the mu–delta and mu–kappa
receptors may lead to enhancement of opioid antinociceptive effects by the
cannabinoids. Consistent with that hypothesis, the heterodimerization of mu–
delta opioid receptor complexes increases the affinity of morphine for binding to
the receptor complex (144). Tolerance does not develop to a low-dose
combination of subactive doses of morphine and THC, and a low dose of THC
will prevent the development of tolerance to morphine (143,145).
In summary, cannabinoids produce antinociception by interfacing with the
opioid system in the control of pain. The mechanisms that underlie such an
interaction between the two systems are clearly involved in the release of
endogenous opioids (particularly dynorphins) by cannabinoids. This interplay of
the cannabinoid and opioid systems suggests the therapeutic potential of these
two drug classes used in combination. Several animal models are being used to
evaluate the complex cannabinoid–opioid interactions and the neurochemical
substrates involved in such interactions and the parallel pathways by which the
endocannabinoids and endogenous opioids control pain (5,6). In addition, the
endogenous cannabinoid system appears to play a role in the suppression of
chronic pain.
Results from Ongoing Phase 1 Clinical Trials

Several phase 1 trials are underway utilizing THC preparations for the treatment
of chronic pain following inhalation (146), as a THC/CBD oromucosal spray to
decrease spasticity due to multiple sclerosis (147), or smoked or vaporized THC
to treat neuropathic pain (for review of literature, see Deshplande et al. (148)). In
the Deshpande et al. review (148), all studies reviewed met consistent statistical
criteria for inclusion due to subjects having neuropathic pain of various origins.
In most studies, the patients were on additional drugs such as opioids for
treatment of pain, which is a potential confound in the results. All studies
indicated that the subjects experienced analgesia that was related to the
concentration of delta-9 THC inhaled, with levels of 7% THC producing the
most consistent relief of pain, but reaching a maximal or “ceiling” effect beyond
which no further analgesia was noted. Adverse effects were similar to those
previously reported for acute and chronic use of cannabis including mild “light-
headedness” (146), sedation, lack of the ability to concentrate, motor deficits,
and minor cognitive deficits. Some subjects noted throat irritation (148). The
adverse effects were apparent even with low doses, but the conclusions were that
generally the THC was well tolerated. As reported by Zetti et al. (147), the
efficacy of the drug depended upon the patients’ perceived severity of spasticity
with the efficacy of the drug being confounded by such perceptions. The drug is
often discontinued in those patients who initially observe no initial amelioration
of symptoms. However, in most studies reviewed, the combination provided
relief from spasticity with a lack of the CB1-mediated effects usually observed
with THC alone such as cognitive deficits or the feeling of being “high.” In
addition, in several studies that were reviewed, the patients did not show signs of
withdrawal upon cessation of the drug. THC has also been evaluated following
intravenous (i.v.) administration in order to determine toxicity in humans (149).
The adverse effects observed were dose-related and similar to those previously
described such as sedation. In addition, the pharmacokinetics of THC i.v. have
been modeled to better predict the metabolism and potential for accumulation
leading to toxicity.
Cannabis use typically precedes involvement with other drugs such as
stimulants. There is no rigorous scientific evidence or known neurobiological
basis for such a “gateway” effect of cannabis smoking. Such an effect may be
due to the increased opportunity of people who use cannabis to associate with
people who use other types of drugs or the group peer pressure to use other
drugs (150,151). A combination of THC and alcohol in humans may result in
increased levels of THC due to ethanol-induced increases in THC absorption,
resulting in enhanced subjective effects on mood (152). This alcohol–THC
interaction may enhance the addiction liability of the drugs in combination. The
acute euphoric effects of cannabis in human studies appear to be due to CB1
receptor activation and are blocked by the CB1 antagonist rimonabant (153).
In preclinical studies, the chronic administration of THC produces
sensitization to the effects of amphetamine and heroin in rats. The rats most
profoundly affected by THC sensitization were those “high-responding” rats
with high intrinsic levels of drug-seeking behavior. These findings suggest a
propensity of THC to increase drug seeking in those individuals particularly
sensitive or vulnerable to addictive behaviors (154).
Human studies of potential pharmacokinetic interactions of tobacco smoking
or tobacco-related products and tobacco cessation in combination with cannabis
smoking or use of THC and CBD have recently been reviewed extensively
(155). The major effect of cannabis smoking is to up-regulate liver metabolic
enzymes also up-regulated by tobacco. The combination of the two classes of
drugs results in an additive increase in one specific liver enzyme that is normally
reduced by smoking cessation. The review discusses the clinical importance of
evaluation of determination of doses of nicotine substitutes, as well as THC-
containing substances in patients using both tobacco and THC to produce a
clinically therapeutic effect.
Conclusions and Future Research

Cannabinoids are a class of compounds with an ancient and rich history of uses
for both recreational and therapeutic purposes. Only within recent decades have
the mechanisms underlying cannabinoid actions been ascertained, aided by the
discovery of receptors, antagonists and endogenous ligands for those receptors,
and new transgenic technology in which the receptors are genetically “removed”
from an animal. Despite these advances in the pharmacology and neurobiology
of the cannabinoids, considerable controversy remains as to their potential
therapeutic uses, as well as the optimum route of administration of THC and
other pharmacologically active cannabinoids.
As described in ancient sources, cannabinoids appear to have a variety of
potentially useful therapeutic effects. The problem that must be addressed by
research is how to develop a cannabinoid or endocannabinoid modulator devoid
of undesirable side effects. Several lines of research indicating non–CB1- and
non–CB2-mediated effects of cannabinoids support the hypothesis that the CB1
and CB2 receptors are not the only cannabinoid receptors. The role of other GPR
“orphan” receptors in human physiology is also a target for therapeutic research.
The increasing knowledge of the ECS’s role in tonic regulation of analgesia,
cognition, food intake, and cardiovascular tone indicates that possible analogs of
the endocannabinoids, or modulators of endocannabinoid pathways, may be
productive targets for drug development. The discovery of the metabolic
pathways of endocannabinoids, which lead to prostanoid-like prostamides and
other metabolites similar in function to prostaglandins and leukotrienes, has
opened another area of research. Allosteric modulation of activated
endocannabinoid binding sites may be an approach to some specificity in the
action of endocannabinoids in disease. The use of
cannabinoids/endocannabinoids in combination with other drugs has become an
area of intense interest. The goal of novel therapeutic interventions will be to
decrease the potential for tolerance and physical dependence. In an excellent
review, Pacher and Kunos (61) have enumerated potential therapeutic
approaches for the use of cannabinoids and modulators of the ECS in disease. In
summary, they conclude that most systems of the body are in some way
impacted by the activation of cannabinoid receptors or the ECS, and thus, the
development of selective ligands for specific diseases will rely upon optimizing
the selectivity of drugs for specific cannabinoid receptors, prevention of
undesirable psychoactive effects by the use of novel peripherally restricted
agonists, and increased knowledge of the interaction of cannabinoid and ECS
with other biological systems including but not limited to the opioids and
prostaglandin synthesis and the interactions with such systems in pathological
states (61).
In summary, the cannabinoids are a class of drugs with a diverse profile of
pharmacological activities. The endocannabinoids and cannabinoid receptors are
highly conserved phylogenically. The research task today remains determining
the reasons for the preservation of the cannabinoid system through both
invertebrate and vertebrate evolution and the roles such receptors, known and yet
to be found, play in diseases, including addictive behaviors.
ACKNOWLEDGMENTS
The authors gratefully acknowledge Julia Moore (www.mooreillustrations.com)
for providing the illustrations in this chapter.
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CHAPTER 16
The Pharmacology of Hallucinogens
Michael P. Bogenschutz and David E. Nichols
CHAPTER OUTLINE
Definition
Substances Included
Features of Clinical Use, Nonmedical Use, and Addiction
Historical Features
Epidemiology
Neurobiology
Pharmacokinetics and Pharmacodynamics
Conclusions and Future Research
DEFINITION
The hallucinogens constitute several highly diverse classes of compounds. In
this chapter, the term will be used to refer to substances whose most prominent
subjective effects include alterations in perception, cognition, affect, sense of
meaning, and/or sense of self. Phencyclidine (PCP) and related
arylcyclohexylamines (such as ketamine), also termed dissociatives or
dissociative anesthetics, are classified as hallucinogen-related substances in the
Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), but
these drugs are treated separately in Chapter 17 of this textbook. Anticholinergic
deliriants, such as atropine, hyoscyamine, and scopolamine, can cause true
hallucinations, but are not typically considered to be hallucinogens and will not
be covered in this chapter.
The term “hallucinogen” is a misnomer in that most of the commonly used
hallucinogens rarely cause true hallucinations. Many other terms have been
proposed. The word “psychotomimetic” has been used to stress the similarity
between hallucinogen intoxication and psychotic illness. However,
hallucinogens have many effects that are not typical of psychosis. The term
“psychedelic” (meaning “mind manifesting”) was coined by Humphrey Osmond
to emphasize the subjective experience of expanded consciousness often
produced by classic serotonergic hallucinogens such as lysergic acid
diethylamide (LSD) (1). The terms “empathogen” and “entactogen” have been
proposed for 3,4-methylenedioxymethamphetamine (MDMA) and related
compounds whose effects are dominated by feelings of emotional openness and
interpersonal connection. The term “entheogen” has been used for hallucinogens
when spiritual or religious aspects of the experience are considered to be of
primary importance.
SUBSTANCES INCLUDED
Basic information about representative hallucinogens is summarized in Table 16-
1, and chemical structures are shown in Figure 16-1. The serotonergic
hallucinogens include what are called the classic hallucinogens, such as
mescaline, psilocybin, LSD, N,N-dimethyltryptamine (DMT), and a large
number of substituted phenylethylamines, such as 2,5-dimethoxy-4-
bromoamphetamine (DOB) and 2,5-dimethoxy-4-bromophenethylamine (2C-B).
Classic hallucinogens possess an arylalkylamine skeleton, either as an
indolealkylamine or as a phenylalkylamine. Agents from this class all bind to
serotonin 5-HT2 family receptors, and of those that have been studied, all are
agonists or partial agonists at the 5-HT2A receptor. Indolealkylamine
hallucinogens include LSD, DMT, and psilocybin and many structurally related
compounds. Hallucinogenic phenylalkylamines include mescaline, DOB, 2C-B,
and a large number of 2,5-dimethoxyphenylalkylamines with various four
substituents such as small alkoxy, small unbranched alkyl, and alkylthio
moieties. Synthesis and preliminary human psychopharmacology have been
catalogued for many of these compounds (2,3).
TABLE 16-1 Representative Hallucinogens

Figure 16-1 Chemical structures or representative
hallucinogens of each class. Structural diagrams are taken
from the PubChem Compound database. (Bolton E, Wang Y,
Thiessen PA, Bryant SH. PubChem: integrated platform of
small molecules and biological activities. Chapter 12. In:
Annual Reports in Computational Chemistry. Vol. 4. Oxford,
UK: Elsevier, 2008:217-240.)
There is another small group of phenethylamines that are similar in structure, but
whose pharmacology differs from the classic hallucinogens. They have been
named entactogens (4), with the prototype being MDMA, and include 3,4-
methylenedioxyethylamphetamine (MDE), 3,4-methylenedioxy-N-methyl-α-
ethylphenylethylamine (MBDB), and the (+)-enantiomer of
methylenedioxyamphetamine [(+)-MDA]. Entactogen is derived from the roots
“en” (Greek, within), “tactus” (Latin, touch), and “gen” (Greek, produce)
connoting substances that “produce a touching within.” Entactogens have a
mechanism of action and subjective effects distinct from the classic
hallucinogens. While these substances affect emotion and promote social
interaction, they do not produce the major alterations in sensory perceptions that
are typical of the classic hallucinogens (5). Although MDMA has significant
stimulant discriminant stimulus properties, MBDB, considered by some to be the
prototypical drug of this class, does not (5). Their ability to decrease anxiety and
increase trust, self-acceptance, and openness has led to research on their use in
treating patients suffering from PTSD (6).
Another hallucinogen unrelated to those described above is Salvinorin A,
which increased in popularity as a “legal high” during the last decade (5).
Salvinorin A is a potent nonnitrogenous (ie, nonalkaloid) substance obtained
from a species of mint, Salvia divinorum. Interestingly, although Salvinorin A
has hallucinogenic effects, it is a specific kappa opioid agonist rather than a
serotonergic agonist.
FEATURES OF CLINICAL USE,

NONMEDICAL USE, AND ADDICTION
Although other recreational drug classes are used principally to become
intoxicated, and at high doses to dull the senses, LSD and classic psychedelics
are more often viewed as having value in self-reflection and introspection.
Indeed, many persons who use these substances consider them to be
“entheogens,” or substances that reveal the god within. For people who use
psychedelics, the experience is about enhancing and expanding perception, and
offering a new way to see the world (7). Jaffe has opined “…the feature that
distinguishes psychedelic agents from other classes of drugs is their capacity
reliably to induce or compel states of altered perception, thought, and feeling
that are not (or cannot be) experienced otherwise except in dreams or at times of
religious exaltation” (8). This definition is certainly unique, has no parallel
among other classes of psychoactive agents, and reflects the type of numinous
experience typically induced in people who use these substances such as LSD or
mescaline.
Clinical Uses
More than 10 000 subjects received hallucinogens, mostly LSD, from 1950 to
the mid-1960s in research settings (7). Initial promotion of LSD by Sandoz
Laboratories, where the drug was discovered in 1943, was focused on the belief
that LSD could induce a model psychosis (ie, was psychotomimetic). Thus,
psychologists and psychiatric staff could experience its effect and better
empathize with what their patients were experiencing. The depth of self-
reflection and introspection they induced, however, led them to be tested in a
variety of psychiatric conditions. In addition, they engendered mystical and
spiritual experiences (9–11). For the most part, the therapeutic model employed,
particularly in Europe, was called psycholytic therapy, where lower dosages of
LSD or psilocybin were used in psychoanalytic settings to facilitate access to
unconscious material. In North America, a somewhat different model called
psychedelic therapy was used, where a large dose was used to provoke an
overwhelming experience, often also producing a mystical experience, for
transformation of personality traits (12,13).
Research on clinical use of hallucinogens focused on investigation of their
effects in the treatment of substance use disorders, particularly alcohol use
disorder, as well as the treatment of pain and end-of-life anxiety and depression
(14,15). A meta-analysis of the six randomized controlled trials of LSD-assisted
treatment of alcohol use disorder conducted in the 1960s found consistent,
persistent (up to 6 months), and clinically meaningful benefits of LSD,
administered at a high dose on a single occasion, over control treatments (16).
Despite the promise that some of these approaches appeared to offer, all clinical
work essentially ended with the criminalization of these substances.
There is now renewed interest in psilocybin and LSD as experimental tools
for elucidating neural mechanisms of consciousness and mood regulation (17,18)
and in their use in the treatment of addiction and other disorders. Randomized
placebo-controlled trials have demonstrated that psilocybin with psychotherapy
can decrease mood and anxiety symptoms in persons with a life-threatening
cancer diagnosis (19–21). Pilot studies have suggested large and clinically
meaningful decreases in alcohol use and smoking following psilocybin-assisted
treatment of alcohol use disorder (22) and nicotine/tobacco use disorder (23,24),
respectively. Another pilot study demonstrated large persisting decreases in
depressive symptoms in patients with chronic major depression following two
administrations of psilocybin (25). Recent studies of the psychotherapeutic
utility of MDMA report significant and enduring clinical improvement in
double-blind, placebo-controlled trials of MDMA-assisted psychotherapy for
patients with PTSD (26). All of these trials have included a significant amount of
psychotherapy prior to and after administration of the substance and carefully
control the environment in which the drug is administered.
Nonmedical Use and Addiction

Nonmedical use of hallucinogens became widespread during the 1960s and was
associated with the social turmoil that was occurring then, most notably focused
around protests against US involvement in the Vietnam War. The extremely high
potency and relative ease of synthesis of LSD led to its ready availability
throughout the Western world. Careless experimentation with these drugs, along
with inexperience among people who use them, led to a wave of complications,
helping to establish a new image of hallucinogens as dangerous drugs (27,28).
These complications included physical injuries resulting from accidents as well
as psychological emergencies that resulted in emergency department visits
(29,30). According to the 2014 National Survey on Drug Use and Health, the
overall rates of hallucinogen use disorders are low compared to other substances
(31), although DSM-IV substance dependence can occur, particularly in those
who begin using hallucinogens at an early age (32).
Hallucinogen use disorder as listed in the DSM-5 and ICD-10 is
characterized by 10 of the 11 substance use disorder criteria included in the
DSM-5 nosology. These criteria include aspects of impaired control overuse,
adverse consequences in various life domains, and tolerance. Withdrawal is not
included as a criterion for hallucinogen use disorder because there is no
established withdrawal syndrome for hallucinogens. The disorder is classified as
mild (2-3 criteria), moderate (4-5 criteria), or severe (6 or more criteria).
Frequent use of hallucinogens leads to a very rapid development of tolerance
known as tachyphylaxis, where daily doses lead to rapidly diminishing effects
until after about 4 days, when the drug no longer elicits any effect (33).
HISTORICAL FEATURES
Hallucinogens have been used ritualistically for millennia in many cultures.
Considerable circumstantial evidence suggests that the Soma of the 3500-year-
old Hindu Aryan Rig Veda and the Kykeon of the ancient Greek Eleusinian
Mysteries were hallucinogens derived from plant sources (34,35). Hallucinogens
also played a prominent role in the cultures of Mesoamerican peoples. For
example, mushrooms of the genus Psilocybe, known as teonanacatl, or flesh of
the gods, were employed ritually by certain native tribes of Mexico such as the
Aztecs. The seeds of Rivea corymbosa, a species of morning glory, also were
used by the Aztec shaman and contain lysergamides (36). Many native people of
Latin America have used DMT-containing plants for spiritual purposes. For
example, DMT is an active component of a powdered snuff from the seeds of
Anadenanthera peregrina and the bark of Virola sp. trees. Ayahuasca is an orally
active DMT-containing plant concoction prepared by boiling pounded
Banisteriopsis caapi vines with leaves from Psychotria, the latter of which
contain DMT (37). Although DMT is not orally active, Banisteriopsis contains
beta-carboline alkaloids (eg, harmine and harmaline) that inhibit the liver
monoamine oxidase (MAO) that would normally break down orally ingested
DMT. Ayahuasca remains an important spiritual medicine of many native people
of the Amazon Basin as well as being a sacrament of the União do Vegetal
(UDV) and Santo Daime churches. The peyote cactus (Lophophora williamsii)
contains the hallucinogen mescaline. It has been venerated for more than 3000
years by the Huichol and Tarahumara tribes of Northern Mexico and also is the
sacrament of the Native American Church (NAC) in the United States and
Canada. The 1994 Amendment to the American Indian Religious Freedom Act
provided legal protection for the use of peyote in the context of Native American
Church Ceremonies. Salvinorin A is a diterpene found in the mint S. divinorum,
a plant originally cultivated in Oaxaca, Mexico, where it has been used for
spiritual and divinatory purposes (38).
Lysergic acid N,N-diethylamide (LSD; LSD-25; lysergide) was first
synthesized in 1938, but its extremely potent psychoactive effects were not
discovered until 1943, when Swiss natural products chemist Albert Hofmann
accidentally ingested a minute amount (39). Following the discovery of its
psychoactive effects, it became a focus of intense interest in psychiatric research.
Serotonin was first detected in the brain about a decade later (40), and it was
recognized that LSD incorporated a tryptamine template, as did serotonin. That
was the point at which it was first hypothesized that serotonin might be an
important neurochemical in brain circuits that mediate behavior (41,42).
By the early 1950s, psychedelics were hailed as a breakthrough for
psychiatry. Studies of hallucinogens, primarily LSD, resulted in more than 1000
publications, describing results from ~40 000 subjects (7). It was used during the
1950s and 1960s as an experimental drug in psychiatric research for producing
the so-called experimental psychosis and in psychotherapeutic procedures
(“psycholytic” and “psychedelic” therapy). Although adverse effects in
laboratory and clinical settings were seldom seen, their recreational use was
accompanied by a variety of adverse events (29). Beginning in about the mid-
1960s, hallucinogens “escaped” from the laboratory and became popular
recreational drugs consumed on a broad scale, particularly in the United States.
They became associated with youthful rebellion, particularly among young
people who protested the war in Vietnam. A number of social and political
factors, as well as media exaggerations, ultimately led to severe restrictions on
access to hallucinogens. The classic hallucinogens were included as Schedule I
substances under the Controlled Substances Act of 1970, meaning that they were
considered to have high potential for unhealthy use, no accepted medical use,
and no accepted safety under medical supervision. By the early 1970s, clinical
research with hallucinogens had effectively stopped completely.
The history of 3,4-methylenedioxymethamphetamine (MDMA, commonly
known as “ecstasy” or “Molly”) is largely separate from that of the classic
hallucinogens. It was first synthesized in Germany no later than 1912 (43).
Alexander Shulgin became impressed with the psychotherapeutic potential of
MDMA in the late 1970s and began making it available to psychotherapists (44).
By the early 1980s, MDMA was becoming a popular street drug, and MDMA
was listed as a Schedule I drug in 1985 (45).
Beginning in the early 1990s, after a hiatus of two decades, renewed interest
developed in the potential therapeutic effects of these substances. The last
decade has seen rapid growth in research on clinical uses of hallucinogens
(summarized above in section on clinical uses). In contrast to the chronic
treatment required for efficacy with conventional pharmacotherapies (eg,
selective serotonin reuptake inhibitors [SSRIs]), these short-term interventions
represent a new paradigm.
EPIDEMIOLOGY
The best available data on rates of hallucinogen use and hallucinogen use
disorders in the United States are from the National Survey on Drug Use and
Health (NSDUH) and Monitoring the Future (MTF) surveys. Data from the 2015
NSDUH (46) and 2016 MTF (47) surveys are summarized below, with further
summary data presented in Table 16-2. 15.3% of the US population aged 12 and
over have used hallucinogens at least once. Rates of past-year and past-month
use in the NSDUH survey are highest in the 18- to 25-year-old age group, and
lowest in the over 25 group. The highest rate of lifetime use is found at age 26-
29 (23.0%), while for past-year use, the peak is at age 19-20 (8.9%), and for
past-month use, the peak is at age 20 (2.4%). Rates of any hallucinogen use
among 12th graders in the MTF study are a bit lower than the rates reported for
18 year olds in the NSDUH survey. The rates are much lower for the younger
age groups (8th and 10th graders). Rates of past-year and past-month use drop
off steadily after age 25. On average, the age at first use was 19.6 years among
individuals under age 50 reporting past-year initiation of hallucinogen use in
2015.
TABLE 16-2 Survey Data on Prevalence of

Hallucinogen Use and Hallucinogen Use Disorder from
the National Survey on Drug Use and Health (NSDUH)
and the Monitoring the Future (MTF) Survey
All numbers represent adjusted percentages of the surveyed sample. Abbreviations: LSD, lysergic acid
diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; DMT, dimethyltryptamine; AMT, alpha-
methyltryptamine; 5-MeO-DIPT, 5-methoxy-diisopropyltryptamine.
aCenter for Behavioral Health Statistics and Quality. Results from the 2015 National Survey on Drug Use
and Health: Detailed Tables. Rockville, MD: Substance Abuse and Mental Health Services
bJohnston LD, Miech RA, O'Malley PM, Bachman JG, Schulenberg JE. “Teen Use of Any Illicit Drug
Other Than Marijuana at New Low, Same True For Alcohol.” Ann Arbor, MI: University of Michigan
News Service, 2016. http://www.monitoringthefuture.org. Accessed April 4, 2017.
cDSM-IV abuse or dependence.
dDSM-IV criteria.
eIncludes PCP and ketamine.
Overall rates of hallucinogen use were fairly stable between 2002 and 2014,
although rates vary significantly across specific age and racial groups and
geographic regions (48). The rate of past-month use for age 12 and greater has
stayed between 0.4% and 0.5%. Among adolescents aged 12-17, it has dropped
from 1.0% to 0.5%. Among young adults aged 18-25, it has ranged from 1.4% to
2.0%. Since 2006, significant increases have been seen in use of DMT, alpha-
methyltryptamine (AMT), or 5-methoxy-diisopropyltryptamine (5-MeO-DIPT),
and S. divinorum. Rates of hallucinogen use are somewhat higher in the Western
United States and in urban counties. Rates of hallucinogen use are highest in
Native Americans, Whites, and those declaring multiple races.
Epidemiological surveys have not collected data on substance use disorder
criteria for various classes of hallucinogen, so little is known about rates of
substance use disorder for most of the individual hallucinogens. Overall,
hallucinogen use disorders are uncommon. Rates of past-year hallucinogen use
disorder are low in all age groups, with an overall rate of 0.1% for any DSM-IV
hallucinogen use disorder and 0.0 for DSM-IV hallucinogen dependence (46).
Hallucinogen use disorders are most common in people under 25, with a peak in
the 18-25 age group (0.3% for any hallucinogen use disorder, 0.1% for
hallucinogen dependence). Among people who used hallucinogens in the past
year, 4.8% of adults and 12.6% of adolescents met criteria for past-year
hallucinogen use disorder.
An analysis of data from the 2005 NSDUH survey examined characteristics
of people who used MDMA in the past year in contrast to those who used other
hallucinogens in a similar time period (including LSD, PCP, mescaline, peyote,
and psilocybin) (49). 1.4% of the adult sample had used one or more
hallucinogens in the past year, and the overall prevalence of hallucinogen use
disorder was 0.11%. Both groups were approximately two-thirds male and aged
25 or younger. People who used other hallucinogens were more likely to be
white than were people who used MDMA. The mean age of first use was 18-19
in both groups. 56% of people who used MDMA and 72% of people who used
other hallucinogens had used <6 times in the past year, with 34% of people who
used MDMA and 22% of people who used other hallucinogens having 12 or
more occasions of use in the past year. Among people who used in the past-year,
4.9% of both groups met DSM-IV criteria for abuse, but 3.6% of the MDMA
users versus 2.2% of people who used other hallucinogens met criteria for
dependence. In a parallel analysis of adolescents who used hallucinogens,
MDMA use was similarly associated with a greater risk of hallucinogen
dependence (adjusted odds ratio = 2.2) (50). These findings suggest that MDMA
confers somewhat greater risk of hallucinogen dependence than does use of
other hallucinogens alone.
NEUROBIOLOGY
Serotonergic hallucinogens (psychedelics) produce an overall activation in the
brain, primarily through effects on central serotonergic systems. Although
classic molecules such as LSD, psilocybin, and mescaline have affinity and
agonist or partial agonist activity at the serotonin 5-HT2 family of receptors (5-
HT2A, 5-HT2B, 5-HT2C), the 5-HT2A subtype is now thought to be the primary
target for all these molecules (51–53). Glennon et al. (54,55) first proposed the
central role of 5-HT2–type receptors for the actions of hallucinogens in animal
models, and Vollenweider et al. (56) later demonstrated that the selective 5-HT2A
receptor antagonist ketanserin could block the effects of psilocybin in humans,
providing strong proof for the mediating role of the 5-HT2A receptor in the
effects of hallucinogens in man. Recently, Quednow et al. (57), using
[18F]altanserin PET, found that the intensity of psilocybin-induced subjective
effects correlated positively with the level of 5-HT2A receptor occupation by
psilocin in the anterior cingulate and medial prefrontal cortices. Psilocin is the
product of in vivo psilocybin dephosphorylation and is pharmacologically active,
whereas psilocybin itself is inactive as a hallucinogen.
Animal models have been used extensively to validate further the conclusion
that 5-HT2A receptors function as the primary mediator of hallucinogen effect.
For example, the head-twitch in mice is a behavior elicited by hallucinogens, but
5-HT2A receptor knockout abrogates this behavior, while specific expression of
the 5-HT2A receptor in forebrain rescues the head-twitch (58). Microinjection of
LSD into the anterior cingulate in rats substituted for systemic LSD in drug
discrimination assays, an effect mediated predominantly by 5-HT2A receptors,
and further suggesting an important role for this brain region in hallucinogen
mechanism of action (59).
The 5-HT2A receptor is highly expressed throughout the cortex, most notably
on apical dendrites of cortical cells in Layer 5. Highest 5-HT2A receptor density
in the brain is found in the claustrum (60,61), but high expression also is seen in
the amygdala, the locus coeruleus, ventral tegmental area, reticular nucleus of
the thalamus, the striatum, and several other important regions (33,60,62,63).
Widespread changes in neuronal excitability resulting from activation of 5-HT2A
receptors in these key brain regions would be expected to have marked effects on
cognition.
The 5-HT2A receptor is a family of A type G protein–coupled receptor
(GPCR). Canonical signaling at the 5-HT2A receptor occurs through coupling to
Gαq, activating phospholipase C, resulting in phosphoinositide hydrolysis,
formation of diacylglycerol, and mobilization of intracellular calcium (64).
Activation of 5-HT2A receptors on glutamatergic neurons within the brain causes
cell depolarization that lowers the threshold for action potential firing, but
generally does not actually generate action potentials (ie, the cells simply
become more excitable). In addition, brain stem dorsal raphe cell firing is
suppressed by psychedelics, either directly (LSD and similar compounds) or
indirectly (by phenethylamine hallucinogens), an effect that also leads to
excitation of the majority of cortical cells (65).
Martin and Nichols (66), using an improved fluorescence-activated cell
sorting (FACS) method to purify hallucinogen-activated neurons from rat brain,
demonstrated that a small subset of 5-HT2A–expressing excitatory neurons (<5%
of the total brain neuronal population) in key brain regions, including the
prefrontal cortex (PFC) and the claustrum, is directly activated by the
hallucinogenic phenethylamine 2,5-dimethoxy-4-iodoamphetamine (DOI). They
also found that other cell types, including inhibitory somatostatin and
parvalbumin GABAergic interneurons, as well as glia and astrocytes are
subsequently recruited. The neurons activated by hallucinogens expressed
significantly higher levels of the gene for the 5-HT2A receptor and are therefore
more sensitive to the presence of hallucinogens than other neurons. Martin and
Nichols hypothesize that the small population of directly responding neurons
may represent a “trigger population” and that activation of these neurons
initiates the cellular events leading to recurrent activity, cortical network
destabilization, and the host of perceptual and cognitive behaviors associated
with hallucinogens.
The differential activation of subsets of both excitatory and inhibitory
neurons that would not occur in a normal conscious brain is expected to alter the
basic function of a given brain area and its ability to communicate with other
regions. Distinct regional cellular populations respond differently to
hallucinogens; thus, different brain regions will be more or less sensitive to their
effects. These cellular effects of hallucinogens most likely underlie the
alterations in brain functional connectivity observed by recent imaging studies.
Although the 5-HT2A receptor appears to be the key target for all of the
chemotypes of serotonergic hallucinogens, LSD and tryptamines such as N,N-
dimethyltryptamine (DMT) or 5-methoxy-N,N-dimethyltryptamine (5-MeO-
DMT) also are potent agonists at the serotonin 5-HT1A receptor, which can
contribute to their behavioral effects in animal models (52).
In addition, all of the serotonergic hallucinogens have agonist activity at the
5-HT2C receptor that is nearly comparable to that observed at the 5-HT2A
receptor (67). There is no evidence that 5-HT2C receptor activation has a
significant role in the behavioral effects of psychedelics, but agonist action at
that receptor can functionally antagonize 5-HT2A receptor activation in an
animal model (68). Finally, LSD is a potent agonist at the dopamine D2 family
of receptors (69,70). It remains unknown whether that action is important to the
profound effects of LSD in humans, but animal models indicate that
dopaminergic effects may be important in the later temporal effects of LSD
(70,71). That is, Daniel X. Freedman, in his early clinical studies of LSD,
described the effects of LSD as occurring in two temporal phases: an early
“psychedelic” phase, followed by a later phase 4-6 hours after LSD
administration, and at times out to 10 hours, where subjects reported “they had
been at the least self-centered, and usually suspicious, with ideas of reference or
even paranoid convictions” (72).
Except for LSD, none of the other serotonergic hallucinogens has been
demonstrated to act directly through dopamine receptors. Nonetheless, it has
been shown using [11C]raclopride PET that psilocybin indirectly increases
dopamine in the basal ganglia (73). Thus, it seems possible that activation of
dopaminergic systems may be a component of the overall psychopharmacology
of hallucinogens.
Repeated administration of hallucinogens leads to a very rapid development
of tolerance known as tachyphylaxis. Daily administration of LSD leads
essentially to complete loss of sensitivity to the effects of the drug by day 4
(74,75). Likewise, daily administration to humans of the hallucinogenic
amphetamine 2,5-dimethoxy-4-methylamphetamine (DOM) also led, by day 3,
to significant tolerance to the drug effect (76). In man, cross-tolerance occurs
between mescaline and LSD (77) and between psilocybin and LSD (78).
Tolerance and cross-tolerance to hallucinogens also develop in animal models
(79–86). Cross-tolerance between the various chemotypes of hallucinogens
supports the notion that the classic serotonergic hallucinogens have a similar if
not identical mechanism of action.
Rapid tolerance to hallucinogens correlates with downregulation of 5-HT2A
receptors. For example, daily LSD administration selectively decreased 5-HT2
receptor density in rat brain (87,88). Not only LSD, but the hallucinogenic
amphetamines DOB and DOI produced 5-HT2 receptor downregulation after
repeated dosing in rats (89). McKenna et al. (90) also reported that chronic
treatment of rats with DOI led to downregulation of brain 5-HT2 receptors. In
vitro agonist-induced receptor internalization has been observed previously for
the 5-HT2A receptor (91,92), and this phenomenon is also observed in vivo in
rats (66).
Brief agonist treatment also led to desensitization of 5-HT2A receptor–
mediated phosphoinositide hydrolysis in transfected cell lines (93–95). Although
the canonical signaling pathway for the 5-HT2A receptor is Gαq coupling and
activation of phospholipase C (PLC), it is now known that several other
signaling pathways can be activated through the receptor. The relative activation
of these different signaling pathways is ligand dependent, has most often been
referred to as “functional selectivity” (and also as ligand bias) (96), and has been
recently reviewed (see, eg, (97,98)).
Glutamate
Research over the past two decades has demonstrated that hallucinogens enhance
glutamatergic transmission in the cortex at the neuronal level and also in
behavioral responses. Aghajanian and Marek (99) reported that serotonin
induced a calcium-dependent rapid and dramatic increase in frequency and
amplitude of spontaneous (nonelectrically evoked) glutamatergic excitatory
postsynaptic potentials/currents (EPSPs/EPSCs) in cortical pyramidal cells of
layer V in rat brain slices. The effect was most robust in the medial PFC and
other frontal areas with a high expression of 5-HT2A receptors in pyramidal
apical dendrites. The specific 5-HT2A antagonist M100907 completely blocked
the effect, as did the AMPA/kainate antagonist LY293558. Reverse dialysis of
LSD for 30 minutes into rat PFC, followed by 45 minutes perfusion with drug-
free solution, led to a significant increase of glutamate that remained elevated for
at least 45 minutes after the LSD perfusion was ended (100). The hallucinogenic
amphetamine DOM (0.6 mg/kg, given intraperitoneally) similarly increased
extracellular glutamate measured in rat PFC.
There also is strong evidence for the interaction of glutamate systems in
serotonin 5-HT2A receptor–mediated behaviors. For example,
intracerebroventricular (ICV) administration of both competitive and
noncompetitive N-methyl-D-aspartate (NMDA) antagonists potentiated the head-
twitch response (HTR) produced in mice by a subsequent ICV injection of
serotonin, providing evidence of glutamatergic modulation of serotonergic
function in living mice (101). Competitive and noncompetitive NMDA receptor
antagonists also markedly enhanced the 5-HT–induced HTR in mice that had
been treated with p-chlorophenylalanine (PCPA) to deplete endogenous
serotonin (102).
Group II metabotropic glutamate (mGlu2) receptor agonists can counteract
the effects of hallucinogenic 5-HT2A agonists. For example, pretreatment of rats
with either competitive or noncompetitive NMDA antagonists enhanced DOI-
induced head shakes mediated by 5-HT2A receptor activation (103). Pretreatment
of rats with LY354740, a mGlu2/3 receptor agonist, attenuated the frequency of
DOI-induced head shakes, whereas the selective mGlu2/3 antagonist LY341495
potentiated DOI-induced head shakes (104). DOI-induced head-twitches in mice
were inhibited in a dose-dependent manner by the selective mGlu2/3 agonists
LY354740 and LY379268 (105). The presynaptic location of mGlu2/3 receptors
suggests that this effect occurs as a result of a presynaptic suppression of
glutamate release, whereas antagonists block the presynaptic autoreceptor
agonist effect of endogenously released glutamate (106).
In rat drug discrimination studies, the effects of phenethylamine
hallucinogens are potentiated by pretreatment with noncompetitive NMDA
antagonists, such as PCP, dizocilpine, or ketamine (107). Additionally,
pretreatment with either the mGlu2/3 antagonist LY341495 or PCP enhanced the
stimulus effect of LSD, whereas the mGlu2/3 agonist LY379268 significantly
but incompletely blocked stimulus control by LSD. Of note, the 5-HT2A
antagonists pirenperone and M100907 completely antagonized stimulus control
by LSD (108).
An in vivo functional interaction between 5-HT2A receptors and mGlu2
receptors has become widely accepted (109), and it has been proposed that the 5-
HT2A receptor forms a heterodimer with the mGlu2 receptor, creating a receptor
complex that serves as a possible site of action for hallucinogenic drugs. 5-HT2A
and mGlu2 receptors directly interact in recombinant cell lines and are present in
the same neuronal cells in culture, and studies suggest this heterodimeric
complex enhances Gαi activation by hallucinogenic 5-HT2A agonists, a signaling
event proposed to be involved in hallucinogen-specific signaling (58,110).
Nevertheless, mGlu2/3 receptors are expressed presynaptically, whereas 5-HT2A
receptors are located postsynaptically, calling into question the possibility of
their coexpression in vivo.
GABA
Most research on effects of psychedelics on amino acid neurotransmitter systems
in frontal cortex has focused on glutamate, but GABA interneurons also play an
important role. Administration of DOI through a microdialysis perfusion probe
in rat medial PFC led to a significant dose-dependent increase in extracellular
GABA (111). Double-labeling immunohistochemical examination of cortical
cells following systemic administration of DOI showed a significant increase in
the number of interneurons expressing both glutamic acid decarboxylase (GAD)
and fos-like immunoreactivity (112). These findings suggest that 5-HT regulates
cortical GABA interneurons, an effect similar to that seen in piriform cortex
interneurons. 5-HT enhanced spontaneous inhibitory postsynaptic potentials
(IPSPs) in rat frontal cortex pyramidal cells through activation of 5-HT2A
receptors located on GABAergic interneurons (113). Additionally, Martin and
Nichols reported that neurons activated by DOI have been found to recruit small
subpopulations (<10%) of inhibitory somatostatin and parvalbumin GABAergic
interneurons (66). Thus, activation of 5-HT2A receptors in the cortex can
produce both excitation and a feed-forward inhibition of cortical pyramidal cells.
Effects on Brain Functional Activity

Evidence from animal and human studies suggests that hallucinogens disrupt
information processing in corticostriatothalamocortical (CSTC) feedback loops
implicated in sensory and sensorimotor gating of internal and external
information to the cortex (114,115). It is widely believed that the thalamocortical
system is critical for conscious activity (116) and that thalamocortical
interactions play a special role in the integration of distributed neural activity
across wide cortical regions and in the generation of conscious experience (117).
The CSTC model proposes that the thalamus plays a key role within CSTC
feedback loops for gating external and internal information to the cortex and
therefore is crucially involved in the regulation of the level of awareness and
attention (114,118).
This view is consistent with the information integration theory of
consciousness (119), which proposes that the thalamus and thalamocortical
system play a crucial role in integrating information and ensuing consciousness.
Hallucinogen stimulation of 5-HT2A receptors located in several key components
of the CSTC loops may alter thalamocortical transmission (114,118). This
interpretation is consistent with neuroimaging studies showing that oral
administration of psilocybin, mescaline, and DMT alter neuronal activity during
their peak effects in the frontomedial and frontolateral cortices
(“hyperfrontality”), basal ganglia, and thalamus (120–123), variously correlating
with different dimensions of psychedelic states (115).
The claustrum is the brain area with the highest expression of 5-HT2A
receptors (60,61). As noted earlier, Martin and Nichols (66) also found that this
region was highly activated by DOI. Reser et al. (124) have suggested that the
claustrum is ideally positioned as a modulator that could desynchronize or
terminate correlated activation of default mode network (DMN)-related areas.
The connectivity and anatomy of the claustrum place it ideally to control
temporal structure of network activity over component cortical areas of the
salience network (125). Torgerson et al. (126) found the claustrum to have the
highest density of fiber connections per unit volume of all brain regions
examined and revealed (a) that the claustrum is a primary contributor to global
brain network architecture and (b) that significant connectivity dependencies
exist between the claustrum, frontal lobe, and cingulate regions.
Blood oxygen level–dependent (BOLD) fMRI and magnetoencephalography
(MEG) have been used to study human brain activity following administration of
psilocybin or LSD. Carhart-Harris et al. (127) published the first study of resting
state functional connectivity (RSFC) in 15 healthy humans after they had
received an intravenous administration of 2 mg of psilocybin. Using arterial spin
labeling (ASL) perfusion and BOLD fMRI, the study revealed decreased
cerebral blood flow and BOLD signal that were maximal in hub regions such as
the thalamus and anterior and posterior cingulate cortex (PCC). Independent
components and seed-based FC analyses revealed increased default mode
network–task-positive network functional connectivity (DMN-TPN FC) and
decreased DMN-TPN orthogonality after psilocybin (128). They hypothesize
that increased DMN-TPN coupling in the presence of preserved thalamocortical
connectivity is related to a state in which arousal is preserved, but the distinction
between inner thought and external focus becomes blurred.
Broadband (1-100 Hz) neural activity using MEG was recorded in 15
healthy volunteers with prior hallucinogen experience who were given
psilocybin (129). The investigators observed decreased oscillatory power after
psilocybin across a broad frequency range, localized primarily to association
cortices, with marked decreases in areas of the DMN such as the PCC. They
found postpsilocybin decreases in oscillatory power in 7/11 brain functional
networks.
Muthukumaraswamy et al. (129) observed broadband desynchronization of
cortical oscillatory rhythms after psilocybin infusion and decreased brain
network integrity. They propose that there may be a general collapse of the
normal rhythmic structure of cortical activity, consistent with the suggestion by
Carhart-Harris et al. (127) that psychedelics disorganize spontaneous brain
activity. The MEG source localizations they found included the PCC, precuneus,
superior and middle frontal gyri, anterior cingulate, and supramarginal and
precentral gyri, hub areas of the association cortex, consistent with previous
fMRI results (127). The PCC in particular showed marked effects that correlated
with the subjective effects of the drug. The suppression of all observed networks
by psilocybin suggested a general disorganization of network-level activity
during resting conditions.
Most recently, Carhart-Harris et al. (130) used ASL, BOLD, and MEG to
image brain activity in 20 healthy human subjects administered 90 μg of IV
LSD. They found visual cortex desynchronization and expanded functional
connectivity in primary visual cortex area V1 to be correlated with visual
hallucinations. Dysregulation of high-level regions and networks correlated with
profound changes in consciousness. Decreased resting state functional
connectivity in the parahippocampus correlated with ego-dissolution and altered
meaning. Their results revealed that resting-state BOLD FC and MEG measures
possess considerable power to predict the psychological effects of LSD. The
effects of LSD on the visual system were pronounced, yet surprisingly did not
correlate with its effects on consciousness. Consistent with their previous
research with psilocybin, a significant relationship was found between decreased
PCC alpha (and delta) power and ego-dissolution. Taken together with results
from their earlier studies, it appears that psychedelics destabilize and disintegrate
normally well-established brain networks and reduce the degree of segregation
between them.
Relative Addiction Liability

As noted above, hallucinogen use disorders are uncommon, but use of
hallucinogens can lead to harmful patterns of compulsive use, and this appears to
be more common with MDMA than with classic hallucinogens (49,50). The
proportion of people who used hallucinogens who also develop hallucinogen use
disorders is considerably lower than the ratios found for most other addictive
substances. For example, this ratio is 10.5% for heroin, 3.4% for marijuana, and
0.65% for hallucinogens (46). Hallucinogens to varying degrees lack two
important characteristics that contribute to the addiction liability of most drugs,
namely, positive reinforcement due to reliably reinforcing effects and negative
reinforcement due to relief of withdrawal. With the exception of MDMA and
similarly acting drugs, the hallucinogens discussed in this chapter are not
consistently reinforcing in humans or in animal models of addiction and in some
cases are aversive (33). The rapid development of tolerance to the effects of
most hallucinogens also limits whatever rewarding effects that they have.
MDMA is reinforcing, though less so than methamphetamine and cocaine
(131,132). However, moderate doses of MDMA do not appear to cause
behavioral stimulant effects or significantly affect extracellular dopamine levels
in nonhuman primates (133). Although hallucinogen withdrawal is not
recognized in the DSM-IV or DSM-5, some people who use MDMA experience
a pronounced “crash” after using MDMA, which in 1% of such people meets
DSM-IV research criteria for withdrawal (134,135).
PHARMACOKINETICS AND
PHARMACODYNAMICS
Because of the large number of compounds in the hallucinogen class, this section
focuses on the hallucinogens whose effects are well characterized (LSD,
psilocybin, DMT, mescaline, MDMA, and Salvinorin A).
LSD
LSD was originally derived from lysergic acid as found in the ergot fungus
Claviceps purpurea. LSD contains an indolealkylamine structure within a
tetracyclic molecule (Fig. 16-1). LSD is often considered the prototypical classic
hallucinogen, and its effects are generally similar to those of the other classic
hallucinogens.
Pharmacokinetics
LSD may be administered by any route, but it is typically taken orally. It is
psychoactive in doses as low as 20 μg (136). Street doses of LSD are extremely
variable, and while 100 μg would be considered a moderate dose, some street
samples may not contain any LSD at all. Following oral administration of 200
μg of LSD, levels peak ~1.5 hours after administration, remain detectable for at
least 12 hours, and are correlated with the intensity of sympathomimetic and
subjective effects (137). The distribution of LSD across tissue and organ systems
has not been quantified in humans, but studies in rats and cats indicate that it
readily crosses the blood–brain barrier (138). Tolerance to autonomic and
psychological effects of LSD occurs in humans after a few moderate daily doses,
probably due to 5-HT2A receptor downregulation or internalization (33).
Pharmacodynamics
Physiological Effects
LSD induces physiological effects including mydriasis, slight increases in blood
pressure and heart rate, vasoconstriction, nausea and vomiting, minimal increase
in core body temperature and blood glucose levels, sweat and saliva production,
and tremor (139–143). Other than mydriasis, these effects occur inconsistently
and are generally not clinically significant. Cardiovascular effects peak about 2.5
hours after oral administration and last for several hours (144), and bradycardia
and hypotension occur occasionally (144). While slight unsteadiness or ataxia
may be observed (145), respiratory drive is unaffected. There is no evidence for
changes in liver and renal function, electrolytes, or blood cell counts (138). In a
recent human laboratory study of the effects of LSD (200 μg orally) versus
placebo, LSD significantly increased blood pressure, heart rate, body
temperature, pupil size, prolactin, oxytocin, and epinephrine and decreased
prepulse inhibition of acoustic startle response (146). Plasma corticosteroids
were increased between 2 and 6 hours after oral LSD administration (147).
Psychological and Subjective Effects

The acute subjective and psychological effects of LSD are unpredictable and can
vary widely from person to person and within the same individual assessed on
different occasions or even at different times during the same occasion (33).
Psychological effects of LSD begin 30-60 minutes after administration, peak
within 2-4 hours, and last between 5 and 10 hours, depending on the dose
(33,144,148).
Commonly observed effects include visual distortions and illusions, altered
perception of time (as time speeding up or slowing down), depersonalization
and/or derealization, and rapid and sometimes extreme changes in mood,
anxiety, weakness, dizziness, unusual bodily sensations, and synesthesias (138).
Insight is usually preserved so that people do not believe these experiences to be
accurate representations of the objective world. However, people may have
unusual thoughts or feelings about themselves or the world, including transient
magical thinking or even delusional ideas. Recent human laboratory studies with
intravenous LSD have demonstrated acute enhancement of mood and increase in
psychosis-like symptoms (149). Two weeks after dosing, no increase in
delusional thinking, but increased optimism and trait openness were observed.
At relatively high doses of LSD and other classic hallucinogens, people may
experience an “alternate reality,” a complete loss of bodily awareness, and/or a
transcendent or mystical experience (33,138). Psychedelic doses of LSD impair
performance on working memory tasks such as digit span and word recall (150)
and have significant effects on psychomotor speed and figure reconstruction
(151). LSD increases creative or unusual responses in word association tasks
(152). There is no evidence for persisting cognitive impairment after LSD intake
(153).
Toxicity/Adverse Effects
The lethal dose of LSD in humans has been estimated to be 1400 mg (154), but
there have been no documented human deaths attributable to toxicity of LSD.
However, impaired judgment in an unsupervised situation can have dangerous
and occasionally fatal consequences. Psychiatric complications including
psychotic episodes have been reported in the context of illicit use (29) but are
extremely rare when LSD is administered in the context of clinical research
(155). Traumatic experiences (“bad trips”) can have long-lasting effects,
including mood and anxiety symptoms and, more rarely, flashback phenomena
(29,156–159). The DSM-5 recognizes hallucinogen persisting perception
disorder as a diagnostic entity characterized by reexperiencing of perceptual
symptoms of hallucinogen intoxication, which persists long after use and causes
significant distress or impairment (160). The number of emergency room visits
related to LSD is relatively low, accounting for just 4819 visits in 2011 (0.2% of
all visits related to substance misuse) (161). However, LSD is not a target of
clinical drug screening. Medical treatment of LSD intoxication is not necessary,
but distressed patients should be managed with calm reassurance and
destimulation (155) (see Chapter 54). Benzodiazepines can be used in cases of
persistent severe agitation or anxiety. Second-generation antipsychotics are 5-
HT2A antagonists and are effective in reversing most of the psychological effects
of classic hallucinogens if all other measures have failed.
Psilocybin and Psilocin

Psilocybin (4-phosphoryloxy-N,N-DMT) and psilocin (4-hydroxy-N,N-DMT)
are substituted indolealkylamines found in many species of mushrooms. The
most commonly used psilocybin-containing mushroom, Psilocybe cubensis,
contains 0.5%-1.1% psilocybin when dried (162). Fresh mushrooms may contain
significant amounts of psilocin, but psilocin is relatively unstable, whereas
psilocybin is very stable at room temperature in dry conditions.
Pharmacokinetics
In rats, ~50% of orally administered C-labeled psilocybin is absorbed via
gastrointestinal tract (163). The vast majority of psilocybin is thought to be
dephosphorylated to psilocin on first pass through the liver, and psilocin is
thought to be the molecule that is primarily active in the brain (164). In humans,
psilocybin and psilocin are detectable in plasma within 20-40 minutes of
ingestion. Within the first 30 minutes, psilocin concentration in the brain on
average is comparable to concentrations with other organs (165). Plasma psilocin
levels peak at about 80 minutes, with substantial individual variation in the time
course of plasma concentration (164). The half-life of oral psilocybin is 163.3 ±
63.5 minutes, and the mean elimination half-life of psilocin is 50 minutes.
Psilocybin has four known metabolites: psilocin, 4-hydroxyindole-3-yl-
acetaldehyde, 4-hydroxyindole-3-yl-acetic-acid, and 4-hydroxytryptophol (164).
Glucuronidated metabolites are excreted by the kidneys.
Pharmacodynamics
Physiological effects within the usual dose range (10-30 mg orally) include
mydriasis, slight acceleration in heart and breathing rate, increased blood
pressure, and hyperreflexia (164,166). Electrolyte levels and blood sugar, liver
enzyme, cortisol, prolactin, and growth hormone levels are unaffected (164).
Psilocybin and Psilocybe mushrooms can cause nausea and vomiting. Mild,
transient headaches are common, with onset occurring near the end of the
intoxication state and usually ending within 24 hours (167).

The effects of oral psilocybin last ~6 hours. The onset of effect is typically
between 30 and 60 minutes, and peak effects are observed between 90 and 180
minutes following oral doses of 5-30 mg (166). The psychological effects of
psilocybin are very similar to those of LSD (see above). Oral psilocybin dose
dependently produces an altered state of consciousness marked by perceptual
changes, intensified emotion, and alterations of thought, time sense, body sense,
and sense of reality and self (166,168). At higher doses, mystical-type
experiences become common, and significant anxiety also becomes more
common.
Toxicity and Adverse Effects

The predicted human lethal dose of psilocybin is 14 000 mg (154), which is
~500 times larger than the typical dose. There are no reports of death directly
caused by psilocybin in the scientific literature. Daily consumption of psilocybin
results in acute tolerance, but such frequent use is virtually unknown (169). As
with other classic hallucinogens, physical dependence and withdrawal symptoms
do not occur (33). There is no evidence of mutagenic or teratogenic effects
(164). Severe anxiety and paranoia can occur even in controlled clinical settings,
but persisting adverse effects have not been reported in clinical studies with
psilocybin. In fact, many participants report that experiences are highly
meaningful and result in lasting psychological and behavioral benefits (170).
DMT
N,N-dimethyltryptamine (DMT) is derived from various plant sources and
animal venoms. It is also produced endogenously in humans in miniscule
amounts (171), although it is not known whether this has functional significance
or is simply a by-product of serotonin metabolism. In addition to its serotonergic
actions, DMT binds to the sigma-1 receptor, which mediates some behavioral
effects in mice (172).
DMT alone is inactive when taken orally because it is almost completely
oxidized by MAO in the gut before it can enter the bloodstream (173).
Therefore, it is administered by smoking of the base form, insufflation or
intravenous injection of the salt form, or orally in combination with an MAO
inhibitor. Ayahuasca is the name given to various plant extracts containing DMT
and β-carboline alkaloids such as harmine, harmaline, and tetrahydroharmine
(174). In the typical ayahuasca brew, leaves of the shrub Psychotria viridis
(containing DMT) and the vine B. caapi (containing β-carbolines) are boiled for
several hours in order to extract the psychoactive constituents. The use of
ayahuasca has spread over the last 40 years from the Amazon rainforest into
urban settings areas of Brazil and parts of Europe, Japan, Canada, and the United
States.
Pharmacokinetics
Pharmacokinetics of DMT vary by route of administration. Peak plasma levels
are reached 2 minutes after IV administration and 1.5-2 hours after oral intake of
ayahuasca (175,176). Once it reaches the bloodstream, DMT is quickly
distributed throughout the body and the brain (177,178). DMT is metabolized
primarily by oxidative deamination (by MAO) and by N-oxidation to indole-3-
acetic acid and dimethyltryptamine-N-oxide (DMT-NO), respectively (173,179).
DMT and its metabolites are eliminated through the kidneys.
Pharmacodynamics
Physiological effects
The acute effects of DMT have been studied in dosages up to 0.4 mg/kg IV
(180), 25.4 mg smoked (173), and 1.76 mg/kg orally as a component of
ayahuasca (181). After IV administration or smoking of freebase, the effects of
DMT begin within 1 minute, peak within 3 minutes, and resolve within 30
minutes (180,182). When it is ingested orally as a constituent of ayahuasca, the
onset of effects begins after 30-60 minutes, peaks within 1-2 hours, and lasts for
about 4 hours (176).
Nausea and vomiting are common with ayahuasca and can occur with oral as
well as with other routes of administration. Intravenous DMT significantly
increases blood pressure (+15-30 mm Hg) and heart rate (+10 bpm) and
mydriasis (180). Cardiovascular effects are less pronounced when DMT is
ingested as ayahuasca (183). IV DMT increases serum levels of prolactin,
growth hormone, ACTH, cortisol, corticotropin, and β-endorphin (175). Unlike
other classic hallucinogens such as LSD, psilocybin, or mescaline, tolerance to
DMT does not appear to develop rapidly in humans (184).

DMT produces alterations in sensation, perception, emotion, sense of self, and
attribution of meaning comparable to those of other classic hallucinogens
(173,180,183). Psychoactive effects of DMT are often very intense, especially
when they appear very rapidly, as with smoking or IV administration. The
psychological effects of DMT are much more gradual in onset with orally
ingested ayahuasca than with other routes of administration, resembling those of
LSD and psilocybin (see Table 16-2).

In high doses, people who use hallucinogens can lose all awareness of their
physical environment and body. Such experiences can be frightening and may
lead to injury or hazardous behaviors due to a grossly impaired perception of
reality. Medical and persisting psychiatric sequelae are rare (185,186). DMT can
cause seizures at high doses; however, there are no known reported cases of
death due to DMT alone or ayahuasca brews not containing admixtures such as
nicotine, belladonna alkaloids, or 5-methoxy DMT. In mice, the LD50 of DMT
is reported to be 32 mg/kg IV (186).
Mescaline
Mescaline (β-3,4,5-trimethoxyphenethylamine) occurs naturally in many species
of cacti including peyote (L. williamsii), which when dried contains up to 4.8%
mescaline (187), and many species of the Trichocereus genus, which may
contain up to 4.7% mescaline (188). Peyote is used as a sacrament by the Native
American Church (189).
Pharmacokinetics
Typical human oral doses are 200-400 mg of mescaline sulfate or 175-350 mg of
mescaline hydrochloride (190). Mescaline is rapidly absorbed in the
gastrointestinal tract and readily crosses the blood–brain barrier (191). Plasma
levels of mescaline and metabolites peak after 2 hours and approach zero by 12
hours. Mescaline is excreted in the urine unchanged (55%-60%) and as
metabolites including 3,4,5-trimethoxyphenylacetic acid (27%-30%), N-acetyl-
beta-(3,4,dimethoxy-5-hydroxyphenyl) ethylamine (5%), and N-acetylmescaline
(<0.1) (191).
Pharmacodynamics
Physiological research on mescaline is quite limited. The duration of action for
mescaline is somewhat longer than that of LSD. Onset of effects is typically 30-
45 minutes after ingestion, and peak effects occur within 2-3 hours, gradually
resolving over the subsequent 4-8 hours (192). Somatic effects are reported to
include increased blood pressure and heart rate, mydriasis, nausea and vomiting,
diarrhea, abdominal cramps, headache, warm and cold sensations, dizziness, and
tremor (192). Prolactin and growth hormone levels increase, with peak increases
between 1.5 and 2 hours after administration (193). Tolerance develops after a
few days of regular, daily usage and resolves after a few days of abstinence
(192).
Subjective Effects in Humans

The effects of mescaline are similar to those of LSD and psilocybin, although
there may be differences in the average effects of these drugs. The limited
comparative studies that have been conducted did not demonstrate significant
differences between mescaline and these other hallucinogens (192,194).

The use of mescaline as a recreational drug is rather limited (195), and medical
emergencies due to mescaline are very rare (161). There is no evidence in the
scientific literature of physical complications or dependency syndromes from
peyote or mescaline, and no serious somatic side effects or fatalities from
mescaline have been reported. Based on animal data, the LD50 of mescaline is
estimated to be 6000 mg (154). There is no evidence of adverse cognitive or
neuropsychiatric effects among Native American Church members who use
peyote regularly in their religious ceremonies (196).
MDMA
MDMA used recreationally is usually taken orally in tablet or powder form. The
content of material sold as MDMA is highly variable, may contain no MDMA at
all, or may include other ingredients such as amphetamines or other synthetic
cathinones (197) or unrelated compounds such as ketamine (198). One common
pattern of use is to ingest MDMA in the context of all-night dance parties or
electronic dance music festivals (sometimes termed “raves”), often combined
with other drugs. Both people who use MDMA recreationally as well as those
with an established MDMA use disorder frequently take multiple doses over the
course of an evening. For all of these reasons, it is difficult to draw conclusions
about the pharmacological properties of MDMA from recreational experience,
and it is difficult to extrapolate findings from human laboratory studies
(controlled dosage of pure MDMA ingested in a standardized setting) to illicit
use of MDMA.
Pharmacokinetics
The effects of MDMA have been studied primarily within a dose range of 80-
150 mg orally. Although this range is considered typical, doses taken by people
who use recreationally may be highly variable due to differences in potency and
content in products sold as MDMA as well as variable methods of ingestion.
People who use MDMA frequently take additional “booster” doses after the first,
to extend or heighten the effects of the initial dose.
After a typical oral dose of MDMA (1.6 mg/kg), plasma levels peak around
1.5-2.5 hours after ingestion and decline gradually over the following 10 hours
(199). In this dose range (125 mg), the half-life is 8.6 hours (200). Excretion is
essentially complete within 24 hours.
MDMA is metabolized primarily by CYP2D6, CYP3A4, and catechol-O-
methyltransferase (201). MDMA itself inhibits CYP2D6, resulting in nonlinear
kinetics, with elevated concentrations and longer half-life with higher doses or
multiple consecutive doses (202).
MDMA metabolites include 4-hydroxy-3-methoxymethamphetamine, 4-
hydroxy-3-methoxyamphetamine, 3,4-dihydroxyamphetamine, and N-hydroxy-
3,4-methylenedioxyamphetamine and the active metabolite MDA (203). The
majority of MDMA is excreted unchanged in the urine with the rest as free
metabolites and conjugated glucuronides and sulfates (204).
Pharmacodynamics
Typical somatic effects of MDMA include anorexia, diaphoresis, mydriasis,
blurred vision, and bruxism (205–207). Blood pressure increases in a dose-
dependent manner with an increase of between 20 and 35 mm Hg systolic and
10-20 mm Hg diastolic in clinically administered doses of 100-125 mg
(201,206). In clinically relevant doses (up to 150 mg), heart rate increases by 10-
20 bpm and body temperature by about 0.4°C. Higher doses can cause increase
in temperature above 28°C, thought to be mediated by norepinephrine release,
increased heat generation, and cutaneous vasoconstriction (208). MDMA causes
acute dose-dependent increases in cortisol, prolactin, vasopressin, growth
hormone, and oxytocin (200,209–211). Acute immunological effects include
reduced CD4 T-cell count, increased NK cell count, and decreased lymphocyte
proliferation (212,213).
Subjective and Psychological Effects

When MDMA is taken orally, the onset of effect is around 30 minutes after
ingestion. With a single oral dose, peak effects occur at around 1.5-2 hours after
ingestion and effects subside over the next 3-4 hours. There is evidence that
females are more sensitive to the effects of MDMA than are males (214,215).
Compared to the classic hallucinogens, MDMA produces mild sensory
effects (eg, pseudohallucinations) as it is only a weak 5-HT2A agonist but
characteristically produces feelings of emotional openness and closeness to
others (5), thought to be mediated primarily by the release of serotonin and
inhibition of its uptake, as well as euphoria and other stimulant-like effects
mediated primarily by release or reuptake inhibition of dopamine and
noradrenaline (214).
Moderate doses of MDMA administered to MDMA-naïve adult research
volunteers produce effects including elevated mood, increased sense of physical
well-being, vague symptoms of derealization and depersonalization, impaired
thinking, and occasionally anxiety (206,207,209). Subjects described a greater
attention to feelings, a higher degree of openness, and increased sense of
closeness to others. In a survey of 500 White American college students who
reported taking MDMA at least once (216), the most commonly reported effects
were euphoria, increased energy, sexual arousal, and feelings of “‘love,’
‘happiness,’ ‘peace,’ and ‘connection.’” Paranoia, anxiety, and depression were
less commonly reported. After the acute effects subside, “hangover” symptoms
may emerge, including dysphoria, fatigue, headache, sore muscles, and
insomnia, lasting for a few hours up to 1-2 days. Clinical studies have
demonstrated acute impairment (217) of sexual drive and functioning during
intoxication, possibly due to prolactin release (218). Some degree of tolerance to
the desired effects may occur with chronic use (219).
In moderate doses, MDMA has relatively modest effects on
neuropsychological performance (220). Additionally, when administered in
doses up to 100 mg, MDMA appears to adversely affect driving performance,
although it may also moderate aspects of driving impairment due to alcohol
(221–224).

The LD50 of MDMA in humans is estimated to be 1875 mg (154). MDMA
appears to be quite safe when moderate doses are administered to screened
participants in the context of clinical research. No significant medical or
psychiatric complications have been reported under such conditions
(26,200,206). However, MDMA ingested recreationally poses significant risks to
those who use them, particularly when high doses are taken in the context of
overexertion and elevated body temperature, for example, at all-night dance
events (“raves”) (225) (see Chapter 54: Management of Stimulant,
Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and
Withdrawal).
MDMA is toxic to serotonergic neurons in animal models, although the
limitations of animal models make it difficult to translate these findings into
humans (226). In humans, studies have demonstrated decreased serotonin
transporter density and cognitive deficits in people with extensive histories of
MDMA use (227). However, these findings are not entirely consistent, and the
implications are difficult to assess due to confounds such as other drug use,
unknown MDMA content of the substance that was ingested, and characteristics
of the people who use MDMA predating MDMA use (228). In animal models,
toxicity appears to be mediated by MDMA’s metabolites, rather than MDMA
itself, and to be potentiated by hyperthermia (229). Low CYP2D6 activity due to
genetics or the presence of enzyme inhibitors diminishes the neurotoxic effects
of MDMA, presumably by decreasing the accumulation of toxic metabolites
(229). Behavioral toxicity has also been reported, and MDMA use can
precipitate anxiety and/or depression (216) and, rarely, psychosis (230–232),
which in some cases may persist for days or weeks.
Other Serotonergic Hallucinogens
Hundreds of serotonergic hallucinogens have been characterized, and new ones
are synthesized every year (see Chapter 21: Novel Psychoactive Substances:
Their Recognition, Pharmacology, and Treatment). Many of these “research
chemicals” find their way to people who use them in unhealthy, non-medical
ways, and they are not always accurately labeled. The effect of most of these
drugs has not been studied scientifically in humans. 2C-B and related
compounds (eg, 2C-E, 2C-I) appear, based on self-reports of people who use
them, to have effects that combine aspects of classic hallucinogen and
entactogen agents (233). Other drugs are reported to have unique effects that
have not been characterized adequately in the scientific literature. Recently, a
number of highly potent hallucinogens with novel structures have been
marketed, which feature strong LSD-like effects and considerably greater
toxicity. For example, 1-(8-bromobenzo[1,2-b:4,5-b′]difuranyl-4-yl)-2-
aminopropane (Bromo-DragonFLY), an agonist at 5-HT2A, 5-HT2B, and 5-HT2C
receptors, is active in doses under 1 mg and has effects that can last for several
days (234). 25I-NBOMe is a highly potent full agonist at the 5-HT2A receptor
(LSD is a partial agonist) and psychoactive in doses of under 1 mg (235). These
drugs appear to be much more toxic than classic hallucinogens (236–238) and
have caused a number of overdose fatalities (239,240), an unfortunately common
occurrence owing to the high potency and novelty of these compounds.
Salvinorin A
Salvinorin A occurs naturally in leaves of S. divinorum, a plant of the mint
family. S. divinorum is used in ritual context by the Mazatec tribe of Mexico by
chewing the leaves or drinking a decoction of the fresh leaves (241). Salvinorin
A is more commonly used recreationally in the United States by smoking the
dried leaves or concentrated leaf extracts of S. divinorum (242).
Pharmacokinetics
Salvinorin A is poorly absorbed orally, as most is degraded in the gastrointestinal
tract (241). When inhaled in vaporized form, blood levels peak at 2 minutes and
then decrease rapidly (243). When given intravenously to rhesus monkeys, the
average elimination half-life was 56.6 minutes and was significantly longer in
females than in males (244). The principal metabolite is Salvinorin B, which is
not psychoactive (245).
Pharmacodynamics
Salvinorin A is a potent, selective kappa opioid receptor agonist (246).
Salvinorin A produces conditioned place preference in rats at 0.1-40 μg/kg,
associated with enhanced dopamine levels in the nucleus accumbens shell. It is
aversive at higher doses (247). Rewarding effects in rats are attenuated by
rimonabant, indicating a role of the cannabinoid CB1 receptor in mediating
reward (247).
Salvinorin A does not have significant cardiovascular effects, and no serious
physiological symptoms have been observed in human laboratory studies at
doses of up to 1.0 mg vaporized and inhaled (248,249). Salvinorin A increased
levels of prolactin and (less robustly) cortisol (243,249).
Subjective and Psychological Effects

When taken orally, the psychological effects of Salvinorin A come on gradually
over 5-10 minutes, plateau for about an hour, and subside over another hour
(241). When smoked or vaporized, the effects from leaves or extracts containing
Salvinorin A can be extremely intense, peak after 2 minutes, and largely resolve
within 20 minutes (248). The subjective effects show considerable overlap with
those of classic hallucinogens but feature some distinctive characteristics
including prominent dissociative and interoceptive effects (248,249). Although
the effects of high doses are somewhat comparable to those produced by
intravenous DMT, people who use Salvinorin A report that their perceptual
world is perhaps even more strangely altered (250,251). Salvinorin A is not
reliably euphorigenic (248,249) and can cause pronounced dysphoria and fear
(251).

There are no published reports of severe physiological toxicity or deaths from
overdose of Salvinorin A. At high doses (1.0 mg vaporized), people who use it
may become completely dissociated and disoriented (252), which can lead to
harmful behavior or apparent loss of consciousness. Harmful physical effects
have not been observed in human laboratory studies. There is little evidence of
S. divinorum causing addiction, and persisting adverse effects appear to be
uncommon (253,254). Persistent psychosis following S. divinorum has been
reported (255,256).
There are few known interactions between the classic hallucinogens and
psychiatric medications. Based on limited retrospective self-reports, tricyclic
antidepressants, lithium, and bupropion may increase sensitivity to LSD, while
SSRIs and MAO inhibitors decrease its effects (257). Because ayahuasca
contains MAO inhibitors, serotonin syndrome is a concern if it is combined with
serotonin reuptake inhibitors (258), although few such cases have been reported.
Several significant drug–drug interactions involving MDMA have been
reported, mostly involving antidepressant medications. Serious complications
from combinations of MDMA with antiretroviral agents have been reported
(259). Citalopram attenuates the psychological and cardiovascular effects of
MDMA, presumably through interaction with the serotonin transporter
(260,261). Because MDMA is metabolized primarily by CYP2D6, medications
that inhibit this enzyme can slow metabolism and increase levels of MDMA.
Pretreatment with paroxetine (a potent CYP2D6 inhibitor) increases MDMA
levels, but still decreases its cardiovascular and subjective effects (262).
Likewise, duloxetine attenuates the physiological and subjective effects of
MDMA and decreases circulating norepinephrine levels, in spite of increasing
MDMA levels (263). Bupropion attenuates cardiovascular effects of MDMA but
increases MDMA levels and duration of subjective effects, while MDMA
increases plasma levels of bupropion (264).
Substances such as alcohol, cannabis, and stimulants are commonly used
together with MDMA (265). Coingestion of stimulants (including caffeine) can
worsen side effects and neurotoxicity of MDMA (265,266). Coadministration of
alcohol prolongs the euphoric effects of MDMA and modestly increases MDMA
levels (267). Alcohol decreases MDMA-induced fluid retention and possibly
attenuates temperature increase, but does not moderate its cardiovascular effects
rate or blood pressure (268).

RESEARCH
The hallucinogens are an extremely diverse group (or groups) of drugs, so there
are few general conclusions that can be drawn about them. What these drugs
have in common is that their most obvious effects include marked alteration in
consciousness. The classic hallucinogens, including LSD, mescaline, psilocybin,
and DMT, are not reliably reinforcing and rarely produce true addiction,
although they can cause significant problems, particularly if used frequently or
carelessly. MDMA, though usually classified as a hallucinogen, has effects very
different from those of classic hallucinogens, including stimulant (amphetamine-
like) effects, and poses enhanced risks and addiction liability, although it appears
to be quite safe in a clinical research context. After many years of neglect, there
is now renewed interest in the possible therapeutic effects of hallucinogens
including psilocybin, MDMA, DMT (ayahuasca), and LSD. New hallucinogens
with higher potency are being synthesized each year, some of which reach the
black market before their effects have been studied. As a result, many of these
compounds represent a significant danger, particularly in comparison to the well-
known classic hallucinogens and entactogens such as MDMA.
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CHAPTER 17
The Pharmacology of Dissociatives
Edward F. Domino and Shannon C. Miller
CHAPTER OUTLINE
Definition (Drugs In This Class)
Substances Included In This Class
Formulations, Methods Of Use
Historical Features
Epidemiology
Pharmacokinetics
Pharmacodynamics
Neurobiology
Conclusions And Future Research
DEFINITION (DRUGS IN THIS CLASS)

Several heterogeneous chemicals are antagonists of the N-methyl-D-aspartate
(NMDA) receptor subtype of the major excitatory neurotransmitter, glutamic
acid, in the brain. Termed dissociatives, these substances can be distinguished
pharmacologically and clinically from true hallucinogens (see Chapter 16). A
simplified view suggests that dissociatives and hallucinogens share common
features; however, hallucinogens affect primarily 5HT2A receptors instead of
NMDA receptors. Hallucinogens are associated with a different 5HT2A-
associated clinical syndrome of intoxication (whereby dissociation or impaired
reality testing is less typically involved and visual hallucinations are more
commonly involved). Dissociatives include various arylcyclohexylamines (of
which phencyclidine [PCP] and ketamine are best known), dizocilpine (MK-80
l), dextromethorphan (DXM), and the gaseous anesthetic, nitrous oxide.
Ketamine and nitrous oxide are used clinically in animals and humans as general
anesthetics, usually in combination with other agents. DXM in small doses is
used clinically as an antitussive in more than 100 over-the-counter cough
preparations.
Most of the known NMDA antagonists are used recreationally in
subanesthetic doses/concentrations. Subanesthetic doses of PCP and ketamine
induce a psychotomimetic state that resembles many but not all of the signs and
symptoms of schizophrenia (1). DXM in large doses is readily metabolized to
dextrorphan (DXO), a significant NMDA antagonist pharmacodynamically akin
to PCP and ketamine (2). Nitrous oxide or “laughing gas” is not typically
classified as a dissociative (more commonly considered an inhalant); however,
given its NMDA antagonist and dissociative-like clinical effect, it merits
inclusion in this chapter.
Dissociatives share the clinical effect of causing a dissociative state of
intoxication that is typically desired by the person using them. The
pharmacology of hallucinogens and other drugs capable of producing psychosis
is discussed in their respective chapters in this section. The specific treatment of
dissociative intoxication and withdrawal states is discussed in Section 6 of this
book.

CLASS
The chemical structures of these arylcyclohexylamines are shown in Figure 17-
1. PCP and ketamine are the principal illicit compounds, and DXM is the
principal over-the-counter compound, contributing to substance use disorders.
Ketamine (Ketalar, Ketalin, Keta, Calypsol, etc.) is a racemic mixture of D- and
L-isomers. The L-isomer is more potent than the D-isomer and is claimed to have
clinical advantages over racemic ketamine. Other members of this class that are
less commonly used recreationally include cyclohexamine (N-ethyl-1-
phenylcyclohexylamine, CI, 400), 1-(1-2-thienylcyclohexyl) piperidine, 1-(1-
phenylcyclohexyl) pyrrolidine, and 4-methyl pip PCP (1-(phenylcyclohexyl)-4-
methylpiperidine). Dextromethorphan (DM, DXM, D-3-methoxy-N-
methylmorphinan) is the D-isomer of a codeine analog, methorphan. In contrast
to the L-isomer, which is an opioid analgesic, DXM is not. The PCP-derived
designer drug N-(1-phenylcyclohexyl)-3-methoxypropanamine and the ketamine
analog methoxetamine should also be included in this class.
Figure 17-1 Chemical structures of major dissociative drugs.
(From Ries RK, Fiellin DA, Miller SC, Saitz R, eds.
Principles of Addiction Medicine. 5th ed. Hagerstown, MD:
Lippincott Williams & Wilkins, 2014. Figure 15-1.)
FORMULATIONS, METHODS OF USE

U.S. Food and Drug Administration–
Approved Formulations
Ketamine (Ketalar) is available as a sterile solution for use in general anesthesia
in both animals and humans as a U.S. Controlled Substances Act Schedule III
substance. It has also been used for prehospital analgesia and anesthesia (3) and
conscious sedation (4). It is used more often in children, who appear less
susceptible than adults to emergent delirium (5). In medical settings, it is
injected intravenously or intramuscularly in doses of 0.1-1.0 mg/kg, depending
on its clinical use. However, it is also effective when insufflated, smoked, or
taken orally. Unhealthy ketamine use can be accomplished by various routes in
different doses. Doses of ketamine as large as 900-1000 mg given intravenously
or intramuscularly are lethal.
PCP is not available as a medical commercial preparation approved by the
U.S. Food and Drug Administration (FDA). It is available in many illicit
preparations in various forms and is used in a wide range of doses. It has many
of the pharmacological effects of ketamine but is more potent, longer acting, and
more likely to produce seizures. Doses of only 120 mg of PCP may cause death.
It has been used as a general anesthetic in animals. It is prepared illegally in
various forms: powder, tablets, and liquid (salt in water, base in ether). The latter
are typically sprayed onto plant leaves such as ginger, marijuana, mint, oregano,
or parsley and then smoked. PCP and some of its congeners are schedule I
substances.
Legal DXM preparations are administered orally. They are usually available
as DXM hydrobromide and less commonly as DXM polistirex. Capsules, tablets,
lozenges, or solutions of DXM hydrobromide are available alone or in
combination with many other substances as cough, cold, and flu relief
preparations. The usual antitussive dosage for adults is 10-20 mg every 4 hours
or 30 mg every 6-8 hours, not to exceed 120 mg daily. Extended release forms
are given as 60 mg twice daily. Larger doses of DXM are used for unhealthy
recreational purposes. DXM has a low toxicity and high therapeutic index (6).
Death is unlikely even at very high doses but has been reported. The additional
ingredients in over-the-counter preparations make for additional hazards:
decongestant/pseudoephedrine (causing cardiac toxicity),
antihistamine/chlorpheniramine (antihistamine toxicity), pain/acetaminophen
(liver toxicity), and bromides (bromide toxicity). A serotonin syndrome has also
been reported (2).
HISTORICAL FEATURES
The discovery of PCP has been well documented by those involved with its
therapeutic development (7). The drug was developed as an intravenous
anesthetic. The unique anesthesia it produced was complicated by a prolonged
emergence delirium. This quickly led to its demise as a clinically useful agent.
PCP is associated with symptoms that model both the positive (delusions,
hallucinations) and negative (blunted affect, ambivalence, asociality, autistic-like
effects) symptoms of schizophrenia, making for perhaps one of the more useful
pharmacological models of schizophrenia (8,9). Its trade name was Sernyl or
Sernylan. Years later, PCP was rediscovered by the recreational drug use
community and has also been known as “PCP,” “angel dust,” “hog,” and
“crystal” (10).
The desirable anesthetic properties of PCP were retained in the short-acting
arylcyclohexylamine derivative ketamine, which produced a briefer emergence
delirium. The term dissociative anesthetic was coined to emphasize that the
anesthetized patient was psychologically “disconnected” from his or her
environment. Ketamine subsequently was discovered by the recreational drug
use community, where it is known as “K,” “super K,” “special K,” and “cat
Valium,” among others. Ketamine has the reputation among people who engage
in unhealthy use as being medically safe because it is made and packaged by
pharmaceutical companies, most often for veterinary use (11,12).
Illicit arylcyclohexylamine use occurs primarily in large metropolitan areas.
Because the drugs are easy to synthesize, they are relatively inexpensive
substitutes for many street drugs. The person using them may not realize that he
or she has used an arylcyclohexylamine because the drugs frequently are
misrepresented as LSD-25, amphetamine, or synthetic marijuana. Moreover,
they may be added to marijuana to enhance marijuana’s desired effects.
In contrast to the arylcyclohexylamines, MK-801 (dizocilpine) was
developed as an anticonvulsant (13) and subsequently was used as a brain-
protective agent; however, it was discarded because of its PCP-like effects (14).
Clinical trials of MK-801 have been extremely limited, and the results are not
easily available. Very little is known of its properties in humans. To date, it has
been impossible to obtain from FDA all of their files on MK-801 via the
Freedom of Information Act.
The history of DXM begins with the synthesis of racemethorphan
(deoxydihydrothebaiodine) or methorphan (Dromoran) and was patented by
Hoffmann-La Roche in 1954 as an opioid analgesic. After the D- and L-isomers
were isolated, it was discovered that the D-isomer was antitussive and had much
less analgesic and narcotic-like properties. DXM is nearly equal to codeine as an
antitussive. However, unlike codeine, DXM is fairly devoid of other opioid
effects such as analgesia, central nervous system depression, and respiratory
suppression. Although it is metabolized to DXO, an NMDA receptor antagonist,
its binding sites in the brain include more than the NMDA receptor. DXM’s
mechanism in low doses as an antitussive is unknown. More basic studies are
needed. In doses of 300-1800 mg (20-120 times the recommended dose), DXM
produces PCP-like mental effects (15,16). However, larger doses (237 times the
recommended dose) are regularly used recreationally (17). Recreational DXM
use has been a concern since at least the 1960s. The over-the-counter tablet form
of DXM, Romilar, was replaced by a cough syrup in 1973 to reduce its
recreational use. In 1990, the FDA Drug Abuse Advisory Committee assessed
DXM use by teenagers and recommended against placing the drug on the
Controlled Drug Schedule but requested more study of the problem (18).
Although recreational use of DXM began originally with liquid cough syrup
(known to hamper the use of large doses of DXM because of the distasteful
nature of cough syrup), more convenient consumer products have since been
developed, including both high-dose (30 mg) tablets as well as high-dose gel
capsules, which are preferred by those who use DXM recreationally. Acid–base
extraction techniques have been developed to “free base” the DXM alone to
facilitate unhealthy use (19). DXM has become popular, particularly among
children and adolescents, owing to this population incorrectly perceiving DXM
as a “SMART” drug to use; that is, they perceive recreational DXM use as
without stigma, not costing much money to procure, having easy access at local
stores, being devoid of medical risks, and not included in routine employment or
home-based drug testing (20). The FDA continues to express its concern over the
recreational use of DXM, in particular the purified powder form purchased via
the Internet (21). Slang terms for the cough medicine preparations are “dex,”
“robo,” “skittles” (owing to some tablets appearing similar to red Skittles
candies), “tussin,” and “triple Cs.” Recreational use of DXM is described as
“dexing,” “roboing,” and “robotripping” (referring to the popular DXM cough
syrup Robitussin).
Nitrous oxide has been known for more than 225 years. It is widely used
today in anesthesia. In addition, its recreational use as “laughing gas” has been
well described since it first was discovered. Ketamine and nitrous oxide still are
medically used in humans as anesthetic agents. Ketamine is used in
circumstances in which other anesthetic agents are relatively contraindicated. In
contrast, nitrous oxide is widely used today as part of the mixture of anesthetics
used to achieve “balanced anesthesia.”
The desirable “brain-protective” properties of NMDA antagonists, including
DXM, have been pursued by the pharmaceutical industry in developing
relatively weak derivatives of amantadine and other so-called sigma receptor
agonists and antagonists (22). For example, amantadine is an antiviral agent used
in the prophylaxis and therapy of influenza A and to treat parkinsonism. Patients
with Parkinson disease who took amantadine reported that it improved their
motor symptoms. The mechanism of action of amantadine is unclear, but may
include dopamine release or blockade of its reuptake and possible muscarinic
anticholinergic action. Amantadine and a related compound, memantine, are
NMDA receptor antagonists (23), but are relatively weak and do not appear to be
recreationally used.
EPIDEMIOLOGY
Unhealthy or recreational PCP use may be more a problem in large cities l than
in the rest of the United States (24). Ketamine is used with other drugs (25);
however, sole use of ketamine has been reported (11) and is now increased all
over the world, particularly in Asian countries (12). Although ketamine has often
been self-administered by insufflation, there is an emerging problem in youth of
injecting ketamine. Such youth are more likely to engage in multiple injections,
shared bottles of ketamine, and use of syringes obtained from secondary sources
—practices that increase risk for hepatitis C, HIV, and other infectious diseases
(26).
DXM is considered one of the most commonly recreationally used over-the-
counter medications in the United States and was first included in the
Monitoring the Future epidemiological surveys in 2006. The proportion of US
students who reported in 2006 having used DXM during the prior year for the
expressed purpose of “getting high” was 4%, 5%, and 7% in grades 8, 10, and
12, respectively (27). Rates in 2011 were similar, at 3%, 6%, and 5%,
respectively (28). 2015 rates dropped slightly (2%, 3%, 5%) (29). Poison
Control Center data from the first half of the 2000-2010 decade reflected
increasing recreational DXM use, particularly among adolescents (30). For
example, cases of DXM use reported to the California Poison Control System
(30) increased 10-fold in all age groups and 15-fold in adolescents between 1999
and 2004. Similar trends were seen in national databases. Approximately 75% of
California cases were aged 9-17 years. The highest frequency of use was in 15-
to 16-year-olds. The most commonly used DXM product was Coricidin HBP
Cough & Cold Tablets. The extent of DXM recreational use is likely far greater
than what has been reported, because only the most severe cases are reported to
poison control databases, and nearly all routine drug screening kits still do not
screen or test for DXM or DXO. Studies of DXM in blood samples of suspected
impaired drivers in the state of Wisconsin between 1999 and 2005 also supported
an increasing prevalence of DXM-positive drivers, with a mean concentration of
207 ng/mL—compared with an expected therapeutic concentration range of 0.5-
5.9 ng/mL (the highest concentrations being in males aged 16-20 years) (31).
Intentional use of Coricidin products reported to the Illinois Poison Center
occurred primarily among adolescents and was associated with significant short-
term clinical effects and $353,314 in-hospital charges annually (2001-2006)
(32). The national upward trend in unhealthy DXM use in the first half of the
decade (2000-2005) has since peaked at 17.6 calls per million population in
2006 and plateaued at 15.7 per million in 2010 (33). A 2004-2013 observational
study of another national poison control database supports that cough medicines
remain the most commonly reported drug class for intentional unhealthy drug
ingestion among all years and regions for adolescents (34).
PHARMACOKINETICS
The pharmacokinetics of PCP in humans have never been well studied with
psychoactive doses using modern methods (6). Blood PCP concentrations from 7
to 240 ng/mL (mean, 75) were found in arrested persons intoxicated in public or
driving under its influence. The blood/plasma concentration ratio is 1. The
plasma half-life (t½) of PCP has been reported to vary from 7 to 46 hours,
suggesting the influence of dose and/or multiphase elimination processes. A
terminal PCP elimination phase (gamma) t½ of 1-4 days has been reported in
cases of severe PCP poisoning (6). PCP is biotransformed in the liver to several
metabolites and excreted in the urine as both free and glucuronide conjugates.
Acidification of the urine increases its renal clearance because is a base.
However, this maneuver is no longer recommended clinically because of the risk
of increasing urinary myoglobin precipitation (35).
The greater lipophilicity of ketamine than PCP accounts for its rapid onset,
short anesthetic duration of action, and shorter period of emergence delirium.
Plasma concentrations of ketamine vary widely depending on the dose, route,
and time elapsed since administration. Anesthetic doses produce plasma or
serum concentrations of 1-6.3 μg/mL.
Nonanesthetic psychoactive blood concentrations of ketamine are in the low
nanograms per milliliter range (100-400). Ketamine follows a three-phase
plasma pharmacokinetic model when given intravenously (6,36). There is a brief
initial (alpha) phase with t½ of about 7 minutes because of rapid redistribution,
followed by a longer elimination (beta) phase with t½ of 3-4 hours. As used in
general anesthesia, an intravenous dose of 2.0 mg/kg produces rapid induction.
This dose produces an onset in 30 seconds, with the coma lasting for 8-10
minutes. The intramuscular injection of ketamine has a latency of 3-5 minutes
and a duration of 10-20 minutes or more, depending on the dose administered.
DXM is readily absorbed from the gut. Peak serum levels are reached at 2-3
hours for immediate release and 6 hours for sustained release preparations. DXO
levels peak at 1.6-7 hours (37). Humans have a genetic polymorphism for the
biotransformation of DXM (6). Rapid metabolizers have a plasma elimination t½
of about 3.4 hours, and slow metabolizers may have t½ exceeding 24 hours. Slow
metabolizers of DXM represent about 10%-15% of the population. Both O- and
N-demethylation of DXO occur, with the N-demethylated version also having
antitussive effects. Subsequent biotransformation results in various less active
compounds. Phenotypic “slow” metabolizers of DXM report fewer intoxication
effects than normal subjects (38). Thus, clinically slow metabolizers might be at
higher risk for developing DXM dependence/addiction (2).
PHARMACODYNAMICS
Depending on the dose and specific arylcyclohexylamine ingested, patients who
have taken PCP or ketamine present with widely different neurological and
psychiatric signs and symptoms. These signs and symptoms can be generally
subdivided into three major clinical pictures: (a) confusion, delirium, and
psychosis; (b) semicoma and coma; and (c) coma with seizures. Patients may
become progressively more obtunded and eventually comatose, or the reverse,
with the patient emerging from coma and showing emergence delirium. Table
17-1 lists the various signs and symptoms of PCP intoxication at different
intravenous doses. Figure 17-2 shows the correlation of the molecular target sites
with doses, concentrations, and clinical effects (39). Most people who use PCP
do not grossly overdose themselves to the point of semicoma and coma. Hence,
most patients intoxicated with PCP show a clinical picture of confusion,
delirium, and psychosis. Rats show marked behavioral sensitization to both PCP
and MK-801, with asymmetric cross-sensitization (40–42). The significance of
this phenomenon for humans is unknown. Whether individuals who use PCP or
ketamine show enhanced psychotomimetic effects over time is also unknown.
Tolerance occurs with PCP and to a greater degree with continuous dosing (43).
Animal models show severe withdrawal after cessation of PCP exposure:
vocalizations, bruxism, oculomotor hyperactivity, diarrhea, piloerection,
somnolence, tremor, and seizures (44). However, human dissociative withdrawal
is not formally recognized by the Diagnostic and Statistical Manual, and human
evidence remains limited (45,46).
TABLE 17-1 Dose-Related Effects of PCP in Healthy

Subjects
Data summarized by Burns RS, Lerner SE. Chapter 21: The effects of phencyclidine in man: a review. In
Domino EF, ed. Phencyclidine: Historical and Current Perspectives. Ann Arbor, MI: NPP Books,
1981:450. (From Ries RK, Fiellin DA, Miller SC, Saitz R, eds. Principles of Addiction Medicine. 5th ed.
Hagerstown, MD: Lippincott Williams & Wilkins, 2014. Table 15-1.)
Figure 17-2 PCP doses, serum concentrations, molecular
target sites, and clinical effects.
Ketamine exists as L- and D-isomers, also loosely chemically designated as the

(S)- and (R)-enantiomers, respectively. It is available in the United States only as
the combination of enantiomers. (S)-Ketamine in vitro has a lower inhibition
constant for the NMDA receptor and a higher one for the sigma-binding site than
does (R)-ketamine (22). (S)-Ketamine is the medically preferred intravenous
anesthetic, especially in Germany and other European countries. There is some
evidence of its superior analgesic potency. About a third of patients in the early
clinical trials of ketamine as a general anesthetic experienced an obvious
emergence delirium (47). Why two-thirds did not remain unexplained, but
suggest the importance of preoperative and postoperative medications, dosage,
environmental, psychological, or genetic factors? People with schizophrenia are
much more susceptible to a prolonged psychotic episode related to PCP than are
other individuals (48). In addition, environmental and genetic factors influence
PCP biotransformation in animals and humans.
During and after slow intravenous administration of 2.0 mg/kg ketamine, the
following sequence of eye signs is observed: blinking, staring, closure of lids,
nystagmus, strabismus, and loss of lid reflex. Initially, when the patient falls into
a dissociative or cataleptic state, the eyelids are widely open and horizontal or
vertical nystagmus is seen. Later, the eyeballs become centrally fixed in a gaze.
During this stage, both somatosensory and visual stimulation elicit evoked
potentials in the cortex. This finding supports the contention that the patient’s
brain cannot interpret the afferent impulses because of the disruption of the
normal connections of the sensory cortex with association areas. The persistence
of open eyes distinguishes ketamine-induced anesthesia from that caused by
other intravenous and inhalational anesthetics or coma-producing substances.
This dissociation between eye signs and anesthetic or coma depth is one of the
major disadvantages of ketamine as an anesthetic agent because eye signs cannot
be used to gauge the depth of anesthesia.
Ketamine induces coma in a dose-dependent manner. A minimum of 0.5
mg/kg intravenously is necessary to induce coma for ~1.5 minutes. A dose of 1.0
mg/kg induces coma for ~5.8 minutes, whereas a dose of 2.0 mg/kg induces
coma for ~10 minutes. Persons who engage in unhealthy ketamine use aim to
achieve the low-dose mental state that is considered reinforcing. One exception
is the giving of large doses surreptitiously to an unsuspecting person, such as in
the illegal act of drug-facilitated sexual assault. The actual rate at which
ketamine is used for this purpose is unknown.
The clinical effects of ketamine are akin to PCP and include analgesia,
dissociation, hallucinations, and anesthesia. Agitation and cardiovascular and
respiratory stimulation tend to be less than with PCP. Violence and unintended
trauma may also result (49). Long-term chronic effects include dysphoria,
impaired memory and cognition, apathy, and irritability (50), as well as
distortion in the subjective experience of time (51). Chronic ketamine use has
been associated with increased serum levels of brain-derived neurotrophic factor
(52). Some anecdotal evidence supports the potential for tolerance and physical
dependence with ketamine, but this needs further study.
In the year 2000, it was reported that subanesthetic doses of ketamine
produced antidepressant effects in depressed patients (53–55). Zarate et al. first
documented controlled clinical trials of ketamine for treatment-resistant major
depression.(56,57). Since then, there has been much research into ketamine and
related molecules as an antidepressant, and despite no FDA approval there has
also been a myriad of ketamine infusion clinics opening to treat depression,
bipolar disorder, post traumatic stress disorder, and other alleged indications—
even though some of these clinics have no expertise in psychiatric or substance
use disorders.
Recently, two Cochrane reviews have been published on the subject. A
review on ketamine for depression (58) found limited evidence for ketamine’s
efficacy at 1 week with less certain effects at 2 weeks posttreatment. Importantly,
no significant results were found for ten similar glutamate receptor modulators.
Risk of bias and the small number of participants eroded confidence in findings.
The authors noted that “many trials did not provide information on all the
prespecified outcomes” and they found no or limited data on issues like
“suicidality, cognition, quality of life, costs to healthcare services, and dropouts
due to lack of efficacy. All included studies administering ketamine
intravenously, which can pose practical problems in clinical practice.” They
concluded that further randomized clinical trials (with adequate blinding) are
needed to explore different modes of ketamine administration with longer
follow-up, better assessment of the comparative efficacy of ketamine, and the
efficacy versus risks of repeated administrations. A second Cochrane review (59)
assessed ketamine for bipolar disorder. Again, results were cause for caution.
There was only a small amount of data usable for analysis; less than for unipolar
depression; and much of the evidence was of low to very low quality. Overall,
they found limited evidence in favor of a single intravenous dose of ketamine
(notably as add-on therapy to mood stabilizers) over placebo and ketamine did
not show any better efficacy in terms of remission in bipolar depression.
Ketamine’s psychotomimetic effects were felt able to compromise study
blinding, and no study used an active comparator. Thus, to enable more robust
conclusions, further randomized clinical trials (with adequate blinding) are
needed to explore different modes of administration of ketamine and to study
different methods of sustaining antidepressant response, such as via repeated
administrations.
Brain electrical activity using magnetoencephalography (MEG) has been
utilized in a few ketamine studies (60). Spontaneous MEG activity postketamine
was the same whether the patients were less depressed or not. However, those
patients who had an antidepressant effect postketamine had increased MEG
activity to finger stimulation, indicating greater cortisol neuronal excitability in
the somatosensory cortex. In a separate NIMH study, blood concentrations of
brain-derived neurotropic factor (BDNF) and electroencephalogram (EEG)
slow-wave sleep increased in the responding subjects (61). Furthermore, blood
levels of the less active metabolite of ketamine were higher in bipolar
nonresponders, indicating the need to measure both ketamine and its metabolite
levels in future research studies.
DXM has significant serotonergic properties, including increasing the
synthesis and release of serotonin, as well as inhibiting the reuptake of serotonin
from the synaptic cleft. DXM in clinical therapeutic doses produces relatively
few side effects. These include body rash, itching, nausea, and vomiting and are
most likely when DXM is combined with the other ingredients in cough
preparations. Depending on dose, the drug can cause drowsiness, dizziness,
altered vision, cardiovascular, and significant central nervous system effects that
may resemble PCP intoxication. Euphoria and hallucinosis can occur within 15-
30 minutes of ingestion of intoxicating doses, with peak effects experienced after
roughly 2.5 hours. Clinical effects of DXM are summarized in Table 17-2 (2).
The intoxication state can persist in varying degrees for about 3-6 hours (called a
“plateau”). Serotonin syndrome can result, especially when taken with other
serotonergic drugs (62). DXO is a stronger NMDA receptor antagonist than
DXM. DXO is relatively inactive at the mu, kappa, and delta opioid receptor
sites; thus, it is essentially devoid of the more conventional opiate properties,
although respiratory depression has been reported with massive ingestion (63).
TABLE 17-2 Characteristics of the DXM Intoxication

Syndrome
aCondition occurs only rarely.

From Bobo WV, Miller SC, Martin BD. The abuse liability of dextromethorphan among adolescents: a
review. J Child Adolesc Subst Abuse. 2005;14(4):55-75. (From Ries RK, Fiellin DA, Miller SC, Saitz R,
eds. Principles of Addiction Medicine. 5th ed. Hagerstown, MD: Lippincott Williams & Wilkins, 2014.
Table 15-2.)
Many centrally acting drugs can produce an additive pharmacodynamic
interaction with all of the agents described herein. Therapeutic combinations of
ketamine with benzodiazepines reduce its emergence delirium, depending on the
pharmacokinetics of the drug involved. Clonidine and related alpha-adrenergic
agonists such as dexmedetomidine have been given clinically with ketamine to
reduce its dissociative effects.
DXM can induce a serotonin syndrome when taken with monoamine oxide
inhibitors, selective serotonin reuptake inhibitors, or other serotonergically
active substances. Genetic polymorphism in the biotransformation of DXM via
CYP2D6 may enhance the toxicity of the former by inhibitors of the latter. These
include many drugs such as chlorpromazine, delavirdine, fluoxetine, miconazole,
paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole, as well as
acute ingestion of large amounts of alcohol.
NEUROBIOLOGY
The action of arylcyclohexylamines on the NMDA type of glutamate receptor
was first described by Anis et al. (64). Other investigators suggested different
mechanisms of action involving biogenic amines and sigma-binding sites
(65–67). However, noncompetitive blockade of NMDA receptors is a primary
mechanism of action of low concentrations of these agents (1). This important
conclusion stimulated interest in the role of glutamic acid in schizophrenia and
related psychotic disorders (68–70). Krystal et al. (71–75) have been especially
active in studying ketamine and possible antagonists in human volunteers.
Moreover, understanding the role of glycine and other agonists in modulating
NMDA receptor function has led to possible novel therapeutic approaches to
schizophrenia (70).
Recent imaging data show that ketamine-induced antagonism of the NMDA
receptor is directly correlated with negative symptoms of schizophrenia
(assessed with the Brief Psychiatric Rating Scale [BPRS] negative subscale),
suggesting that dissociatives may induce negative symptoms via NMDA
antagonism (76). It has also been hypothesized that dissociatives induce positive
symptoms via enhancing glutamate release. As discussed by Deakin et al. (77),
Olney and Farber (78) previously suggested that NMDA antagonists block
excitation of gamma aminobutyric acid (GABA) interneurons (79), resulting in
removal of GABAergic inhibition of cholinergic, serotonergic, and glutamatergic
afferents to the posterior retrosplenial cingulate cortex. This suggests a
mechanism for excitotoxicity and the subsequent posterior cingulate pyramidal
cell neurodegeneration observed after PCP administration. Subsequent studies
using in vivo microdialysis confirmed that the administration of NMDA
antagonists increased glutamate release in the frontal cortex. Alternatively,
mGluR2 (metabotropic glutamate 2/3 receptor) agonists, acting presynaptically
to decrease the release of glutamate, reverse the behavioral effects of PCP in rats
(80).
Ketamine administration induces a rapid, focal decrease in ventromedial
frontal cortex regional blood oxygenation level–dependent (BOLD) fMRI
signals that strongly correlate with its dissociative effects. This results in
significantly increased BOLD activity in the mid-posterior cingulate, thalamus,
and temporal cortical regions—increases correlated with BPRS psychosis scores
(77). Pretreatment with lamotrigine (a sodium channel blocker that decreases
glutamate release) prevented many of the BOLD changes and increases in BPRS
psychosis scores. Thus, dissociatives may induce positive symptoms via
enhancing glutamate release (77). There may be other mechanisms at play that
relate to the association of positive and negative symptomatology with
dissociative exposure.
Because ketamine is classified as a general anesthetic, it has typically been
administered in experimental antidepressant trials by an anesthesiologist infusing
a single subanesthetic intravenous dose, followed by at least 24 hours of
inpatient observation (81,82). Most adverse effects have been mild, without
significant changes in blood pressure, pulse, or respirations noted. While
ketamine and dissociatives remain a promising area of research for depression,
limitations remain (few randomized controlled trials exist, an active placebo is
typically lacking, long-term data are scant, and risks remain uncertain). Thus,
this approach remains experimental. Proposed mechanisms for the rapid
antidepressant action of ketamine include ketamine-mediated blockade of
NMDA receptors at rest, resulting in release of BDNF. Previous studies suggest
increased BDNF function as one possible mechanism of action for traditional
antidepressants (82).
The action of nitrous oxide as an NMDA antagonist is another major
advance in our knowledge (83–85) that may have clinical applications (83–85).
Nitrous oxide is thought to stimulate the neuronal release of endogenous opioid
peptide or dynorphins; the molecular aspects of this process are as yet unknown
(86). Moreover, nitrous oxide may have an excitatory action on neurons via
GABA-A receptor–mediated disinhibition (87).
Addiction Liability
Why these substances are reinforcing is difficult to understand (as they are not
reported by people who use them as eliciting a state of pure euphoria), except in
the context of individuals who wish to experience the feelings of floating in
space, dissociation, sensory isolation, mental distortions, and so forth that
dissociatives provide. Dissociatives are self-administered by animals. Rhesus
monkeys self-administer PCP, and social stimulation among monkeys in
adjoining cages enhances reinforcing strength of PCP (88). Changes in
dopaminergic or cAMP signal cascades induced by single or repeated PCP doses
in mice likely play a role in the development of PCP-induced rewarding effects
(89). Rodent and primate animal studies of DXM support reinforcement by
DXO, akin to PCP. Stimulus discrimination from DXO and stimulus
generalization to PCP are reported for DXM. Moreover, DXM is also strongly
self-administered by animals (90).
Very little work has been done to develop medications to treat dissociative
addiction (91). Reformulation of DXM preparations may reduce liability for
unhealthy use (92). An anti-PCP monoclonal antibody for PCP addiction is
under development (93).
Since the 1970s, when Olney described the neurotoxic effects of glutamic acid,
reducing its excess has been a target for brain-protective agents. NMDA
antagonists have remarkable effects on brain neurons (94), including toxicity
(95), that can be reduced or prevented (96). These agents induce significant
vesicular changes (termed Olney lesions) in rat brain posterior cingulate
retrosplenial neurons. Not all species of animals evidence these changes. The
relationship of such neurotoxicity to humans who engage in unhealthy use of
NMDA antagonists remains unclear. Such neurotoxic changes are reduced by
pretreatment with benzodiazepines, further supporting the mechanism of NMDA
antagonists blocking GABA interneuron activity, resulting in disinhibition of
cholinergic, serotonergic, and glutamatergic afferents—resulting in
excitotoxicity. Such vesicular Olney lesions are not evident in DXM toxicity in
rats (97). However, repeated high-dose administration of DXM during
adolescence in rats may induce permanent deficits in cognitive function;
increased expression of NMDA receptor AR 1 subunits in the prefrontal cortex
and hippocampus may play a role in these DXM-induced memory deficits (98).
This has troublesome implications in the setting of the increasing prevalence of
unhealthy DXM use in adolescents coincident with a remarkable period of brain
growth during this age period. For example, young children iatrogenically
exposed to dissociative anesthetics might have later onset of learning disorders
(99). Human studies show impairments in working and episodic memory, among
other cognitive problems, correlating with ketamine exposure levels (100).
Further supporting problems with working memory and other cognitive issues,
people who use ketamine chronically, compared to controls, show less bilateral
dorsal prefrontal gray matter, with duration of use negatively correlating with
gray matter volume and estimated total lifetime consumption of ketamine
negatively correlating with gray matter volume in the left superior frontal gyrus
(101) (see Fig. 17-3). This same research group found white matter
abnormalities in bilateral frontal and left temporoparietal cortices, with
anisotropy values negatively correlating with the total lifetime ketamine
consumption, indicating pathology of the white matter/axons in these brain
regions (102) (see Fig. 17-4). The temporoparietal area integrates data between
that which is external to the body versus internal, and thus has been implicated
“out-of-body” experiences, thus lending support for the dissociative effect of this
drug class. Studies using dissociative drug intoxication as a model of cognitive
dysfunction in schizophrenia to develop new pharmacotherapies may also reveal
solutions for the cognitive consequences of chronic dissociative use (103,104).
Figure 17-3 Brain maps of representative axial slices
showing the differences of gray matter (GM) volume
between the ketamine-use group and control group. Voxels of
reduced GM volume in bilateral frontal cortex, including left
superior frontal. (From Liao Y, et al. Reduced dorsal
prefrontal gray matter after chronic ketamine use. Biol
Psychiatry. 2011;69(1):42-48.)
Figure 17-4 Brain maps of representative axial slices
showing regions of abnormal fractional anisotropy in patients
with ketamine use in relation to healthy comparison subjects.
(From Liao Y, et al. Frontal white matter abnormalities
following chronic ketamine use: a diffusion tensor imaging
study. Brain. 2010;133(7):2115-2122.)
Intoxication and Overdose

Intoxication is discussed in greater detail in Section 6 of this book. Although a
preliminary diagnosis of arylcyclohexylamine intoxication can be made on the
basis of history, clinical signs, and symptoms, confirmation of exposure via a
drug-positive blood or urine specimen is helpful. Most clinically used drug
screening panels include PCP but not the other agents discussed herein; thus, a
request may be required for specialized testing. A large variety of different
chemical assays are available, but gas chromatography–mass spectrometry is
often ideal for confirmation (105).
The brain wave changes induced by arylcyclohexylamines are unusual, and
an EEG can be helpful if the patient is uncooperative or comatose. Serum
skeletal creatinine phosphokinase levels are increased, and the urine can contain
myoglobin because of rhabdomyolysis. End-organ kidney damage may result.
The first step in the differential diagnosis of arylcyclohexylamine
intoxication is identifying whether the patient is in coma with or without
seizures, emerging from coma, descending into coma, or in a psychotic state.
The patient in coma—with or without seizures—has a differential diagnosis that
includes all other causes of coma and seizures. The history and laboratory
analysis are crucial. This is further discussed in Section 6 of this book.
Psychotic manifestations of arylcyclohexylamine poisoning can be confused
with catatonic schizophrenia, an acute toxic psychosis induced by hallucinogens,
and various acute organic brain syndromes. Arylcyclohexylamine intoxication
can induce an organic brain syndrome, as well as cardiovascular and renal
complications that are seldom, if ever, seen with other psychiatric syndromes.
Lower urinary tract symptoms are common, including severe pain, frequency,
hematuria, and dysuria (106). Body image loss (especially numbness of the
entire body), feelings of being in outer space, and (less commonly) visual
hallucinations suggest arylcyclohexylamine use, as opposed to classic
hallucinogens such as LSD-25 or related agents. DXM is associated with
psychosis at doses greater than 300-600 mg or in fast metabolizers of DXO (17).
Psychosis may occur at lower doses when DXM is combined with other drugs
such as alcohol. Folate deficiency may also be associated with unhealthy DXM
use (107). Unhealthy DXM use may result in brain damage, seizure, loss of
consciousness, irregular heart beat (21), and death. Respiratory depression from
DXM may be reversed with naloxone (108). An evidence-based consensus
guideline for out-of-hospital management of DXM toxicity is available (109).
Although DXM has obvious toxicity, it may hold promise for antidepressant
effects (110).

RESEARCH
Dissociatives include an array of compounds sharing antagonist activity at the
NMDA receptor (among other actions on the human brain) and resulting in a
clinical syndrome involving dissociation or disconnection of the brain from its
external and internal environments. Such a disconnection is described by people
who use dissociatives as the desired end state when engaging in unhealthy use of
these compounds; however, it is not uncommon for people to exceed the dosing
required for these effects, resulting in untoward psychiatric and medical effects.
It is often only then that such patients present for medical assistance. Antidotes
or other effective treatments do not yet exist for these compounds, making
supportive care the basic treatment modality. The addiction liability of these
drugs requires further exploration, particularly in light of current off-label use as
an antidepressant in psychiatrically compromised patients. The evaluation of this
drug class for its neuroprotective qualities may prove increasingly fruitful as the
world population increases in average life span, and the need for such future
agents increases as well. The possible rapid antidepressant qualities of ketamine
infusion are a recent discovery resulting in increased research (57), with interest
in extending this research to DXM (110). Possible future expanded clinical use
of ketamine as an antidepressant raises concern for future ketamine/dissociative
unhealthy use from a not-so-novel group of people already at risk for substance
use disorders—depressed individuals. Finally, the increasing prevalence and
significance of recreational/unhealthy DXM use is alarming, particularly for the
concentrated involvement of young people who appear unaware of its potential
toxicities. Preliminary data suggest neuronal toxicity, and resultant
neuropsychological impairment may result from DXM exposure, particularly in
the adolescent, developing the brain. Public policy may be increasingly directed
toward controlled access to DXM versus its current over-the-counter (or behind
the counter) availability.
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109. Chyka PA, et al. Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-
hospital management. Clin Toxicol. 2007;45(6):662-677.
110. Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Med Hypotheses.
2011;76(5):717-719.
CHAPTER 18
The Pharmacology of Inhalants
Robert L. Balster
CHAPTER OUTLINE
Definition
Substances Included in This Class
Historical Features
Epidemiology
Pharmacokinetics
Pharmacodynamics
Addiction Liability
Future Research Directions
DEFINITION
There is good consensus on what constitutes unhealthy inhalant use. Typically,
inhalants used in such a manner are breathable chemicals that can be self-
administered as gases or vapors. The products can be gases, liquids, aerosols, or,
in some cases, solids, but products that begin as liquids or solids are vaporized
and inhaled. There are historical examples of liquids that are both inhaled and
consumed orally (eg, ether), but the overwhelming majority of these inhalants,
by definition, are inhaled. Drugs such as crack cocaine, which is aerosolized, and
cannabis, which is smoked, are consumed by inhalation but are not generally, or
usefully, classified as inhalants. Neither is inhaled nicotine from e-cigarettes.

CLASS
With other drugs, it has proved most useful for addiction medicine to classify the
substances primarily on the basis of shared pharmacological and behavioral
effects rather than by structure, source, or form. It would be desirable if the same
could be done for inhalants (1). The problem is that there is no sufficient
knowledge of the effects of inhalants to make fine distinctions among them. In
addition, the toxicological effects of these compounds differ, and these
differences do not necessarily follow classifications based on acute unhealthy
use-related pharmacological and behavioral effects. In addition, a single factor
has not been shown to describe DSM-5 inhalant use disorder, regardless of the
class of inhalant being used (2). Nonetheless, three pharmacological
subdivisions of inhalants are useful, as shown in Table 18-1. The rationale for
this subclassification has been presented elsewhere (3) and is summarized below.
TABLE 18-1 Pharmacological Classification of

Inhalants
Volatile Alkyl Nitrites

The prototypic alkyl nitrite is amyl nitrite, used medically as a vasodilator for
treatment of angina. Amyl nitrite is available as a volatile liquid in glass
ampoules that are broken open and the vapor inhaled. At one time, the ampules
were available over the counter, and people would “pop” them open—hence the
street name “poppers.” When amyl nitrite was brought under prescription control
by the U.S. Food and Drug Administration (FDA), retailers made room odorizer
products from other alkyl nitrites with names such as “Locker Room” (nitrites
smell like a locker room), “Rush,” “Hardware,” and “Climax.” The latter
connote their use in the context of sexual activity. As of this writing, cyclohexyl
nitrite appears to be the most easily obtained volatile nitrite. Very little is known
about the safety of these products. Interestingly, dietary supplements and other
concoctions without nitrites are now being sold as performance enhancers using
the brand names used previously for poppers.
Relatively little research has been done to determine the mechanisms of
action for volatile nitrites. It is clear from animal studies that they do not
produce acute intoxications similar to those of solvents such as toluene. It seems
likely that they are used because of their ability to produce syncope secondary to
venous pooling in the periphery and because of their effects on tumescence and
smooth muscles, making them popular as aids to sexual activity. The
attractiveness of syncope as a drug effect might be questioned until one recalls
that even children like to hold their breath or twirl around until dizzy.
Nitrous Oxide
Nitrous oxide is somewhat distinct in that it is a gas at room temperature and
pressure. It is popular to divert anesthetic nitrous oxide for illegitimate use. The
tanks can be used to fill balloons for ready sale at concerts or parties. Nitrous
oxide can also be obtained from whipped cream dispensers; adapter
paraphernalia is available to facilitate self-administration of the gas from the
pressurized cans. The acute pharmacological and behavioral effects of
subanesthetic concentrations of nitrous oxide are poorly understood. It can
produce euphoria (“laughing gas”) and feelings of intoxication (4), but the
qualitative nature of this intoxication appears to be different from that produced
by anesthetic vapors such as isoflurane and sevoflurane (4,5). It should be
remembered that nitrous oxide is very impotent as an anesthetic, requiring
concentrations of about 15%-20% to produce intoxication. In fact, many people
who use it breathe almost 100% nitrous oxide (eg, from a balloon). This action
can lead to anoxia and, as with nitrite-produced syncope, has acute
psychological effects as well.
Another interesting aspect to nitrous oxide pharmacology is that, unlike
vaporous anesthetics, it can produce good analgesia, as seen in animal models,
and there is some evidence for opioid receptor involvement in the analgesic
effects (6), although opioid antagonists do not appear to reverse either anesthesia
or subanesthetic intoxication with nitrous oxide (3). GABAergic or NMDA
antagonist effects have also been proposed as mechanisms for various effects of
nitrous oxide (6,7).
Volatile Solvents, Fuels, and Anesthetics
This category includes a large collection of chemicals, which further research
probably will reveal to have different profiles of acute effects as well, but the
state of the science is insufficient at this point to propose a further
subclassification. Among the prototypic chemicals for this class are toluene and
other alkyl benzenes, butane and other alkanes, R134a (1,1,1,2-
tetrafluoroethane) and R152a (1,1-difluoroethane) and other haloalkanes, and
various ketones, alcohols, and ethers (see Table 18-1). It has been hypothesized
that many of these commercial chemicals share profiles of acute effects with
subanesthetic concentrations of volatile anesthetics such as halothane,
sevoflurane, and isoflurane (8,9). These anesthetics offer a safer alternative to
the study of toluene and similar chemicals in humans, and they have been
directly compared in many animal studies (8,9). As a point of comparison, it is
useful to recall that beverage alcohol (ethanol) also is a solvent and produces a
type of anesthesia at very high blood levels. Ethanol is much less potent than the
other solvents for acute central nervous system (CNS) effects, discouraging use
by inhalation because it is difficult to produce intoxication without heating, a
dangerous practice. Alcohol shares pharmacological and behavioral effects with
depressant drugs such as the barbiturates, nonbarbiturate sedatives, and
benzodiazepines, and perhaps unhealthy use of these solvents and anesthetics
could be viewed clinically as special instances of unhealthy use of depressant
drugs (10). To be sure, the acute depressant-like intoxication and presentation of
overdose can be the same among all these compounds.
HISTORICAL FEATURES
History
The unhealthy use of inhalants has a long history. Perhaps the best known
instances are the use of anesthetics for purposes of intoxication that began with
their discovery more than 200 years ago. The euphoriant effects of nitrous oxide
were noted by Sir Humphrey Davy, who synthesized the substance in 1798 and
began calling it “laughing gas.” Laughing gas subsequently was used as part of
comedic traveling shows at the beginning of the 19th century. The early vapor
anesthetics, including ether and chloroform, were used recreationally and as
“nerve tonics,” both by inhalation and drinking. It may seem odd to drink an
anesthetic, but one must remember that alcohol is a highly volatile liquid with
irritant properties, yet its oral consumption surprises no one.
Today, these inhalants differ widely in their availability. Some, such as
nitrous oxide and amyl nitrite, are under control of the FDA as prescription
medications, although forms of nitrous oxide are available commercially.
Commercial sales of volatile alkyl nitrites are regulated in the United States by
the Consumer Product Safety Commission, a step that has greatly reduced the
availability and unhealthy use of most of these substances. However, nitrites are
still advertised for sale on Internet sites. Many other types of inhalants used in
unhealthy ways can be found in homes or workplaces or are readily purchased at
retail establishments. Gasoline, a very complex mixture of volatile compounds,
is available everywhere, and butane lighter fluid is easy to obtain. Although
inhalants are not regulated under the Controlled Substances Act or by
international treaty, several states have enacted restrictions on the sale and
distribution to minors of certain products that are commonly used as inhalants.
Some states have introduced fines, incarceration, or mandatory treatment for the
sale, distribution, use, and/or possession of inhalant chemicals. There have been
discussions of strategies to prevent access to inhalants, to change their labeling,
or to reformulate products to limit their potential for unhealthy use. Each of
these strategies needs to be viewed on a case by case basis to be certain that it
will achieve the desired effect and not result in people seeking potentially more
toxic products that almost certainly cannot be restricted (eg, gasoline). Harwood
(11) has undertaken a policy analysis of the inhalant problem in the United
States, including the roles of treatment and prevention.
EPIDEMIOLOGY
More than 22 million Americans aged 12 or over have used inhalants, and every
year, about 750 000 use them for the first time (12). Results of national surveys
suggest that the prevalence of inhalant use is greatest among 12- to 17-year-olds
compared to other age groups. The school-based Monitoring the Future national
survey in the United States of 8th, 10th, and 12th graders (13) estimated that
rates of inhalant use in 2015 continued to show a steady decline from their peak
in the mid-1990s, yet it still remains high (Fig. 18-1). One important difference
from other drugs is that the prevalence of inhalant use actually decreases from
8th to 12th grade. Except for alcohol and tobacco, the prevalence of inhalant use
among youth is second only to marijuana in this age range. The 2014 U.S.
National Survey on Drug Use and Health estimated lifetime, past year, and past
month prevalence for marijuana, inhalants, and cocaine in the United States (14).
About 1 in 20 youths used inhalants sometime in their life, and 2.1% used them
in the past year (Fig. 18-2). Among older youth and adults, the prevalence of
inhalant use falls considerably below that of marijuana, cocaine, and heroin, but
those who engage in unhealthy inhalant use remain a significant minority of all
people who use substances. It is particularly prevalent among juvenile–justice
involved youth (15). Although many people who use inhalants quit as they reach
young adulthood, it is incorrect to characterize this problem as a passing fad in
youth. For about half of people who use currently, duration of use exceeds 1-2
years, with about 10% using inhalants for 6 years or more (15). Unhealthy use of
inhalants is an even more significant problem in other parts of the world,
particularly in low and middle income countries (16).
Figure 18-1 Trends in the annual prevalence of the use of

inhalants for 8th, 10th, and 12th graders in the United States.
Shown here is the estimated use in the past year during each
of the reporting years from 1996 to 2015. (From Johnston
LD, O’Malley PM, Bachman JG, Schulenberg JE.
Monitoring the Future National Results on Adolescent Drug
Use 1975-2015: Overview, Key Findings on Adolescent Drug
Use. Ann Arbor, MI: Institute for Social Research, University
of Michigan, 2016.)
Figure 18-2 Lifetime, past year, and past-month prevalence
estimates for marijuana, inhalant, and cocaine use in 2015 for
youth aging 12-17 in the United States. Based on data from
the National Household Survey on Drug Use and Health.
(Center for Behavioral Health Statistics and Quality. 2015
National Survey on Drug Use and Health: Detailed Tables.
2015.
http://www.samhsa.gov/data/sites/default/files/NSDUH-
DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-
2015.pdf. Accessed November 8, 2016.)
People who use inhalants often develop substance use disorders (SUDs). In one
study (17), 8% of people who used inhalants in the past year (18 years and older)
met the DSM-IV criteria for inhalant abuse or dependence within that period.
Inhalant use is also associated with other SUDs and may be an even stronger
predictor of subsequent substance-related problems than marijuana use. Several
studies have shown a clear progression from early inhalant use to later use of
drugs such as cocaine and heroin. In one such study, researchers found that
youth who had used inhalants by age 16 had more than a ninefold greater
likelihood of using heroin by age 32 than did youth who had not used inhalants,
even when controlling for other risk factors associated with inhalant use (18). In
another study, a history of inhalant use independently increased the odds of
becoming a person who uses injection drugs by more than fivefold (19). In the
latter study, the magnitude of the increased risk associated with inhalant use
exceeded that for marijuana use. There is also evidence that people who use both
inhalants and marijuana are at especially greater risk. For example, among
adolescents who had used both (20), 35% had a 1-year prevalence of DSM-
defined alcohol abuse or dependence and 39% had an SUD.
PHARMACOKINETICS
Inhalants include compounds that are self-administered as gases, vapors, and
aerosols. These three forms of inhalants have somewhat different absorption
characteristics and require different methods of use (eg, balloons for gases and
bags or rags for volatile liquids). In the case of aerosol products such as spray
paint, the likely “active ingredient” for people with inhalant use disorder is the
propellant (eg, butane) that exists in the aerosol can under pressure; however, the
other materials in the cans (eg, pigments) also can be absorbed.
A useful way to think about the bioavailability of inhalants is to apply
knowledge of inhalation anesthesia. Gases and vapors rapidly penetrate deep
into the lung and, because of their high lipophilicity, are rapidly absorbed and
distributed into arterial blood. What distinguishes unhealthy inhalant use from
anesthetic use is that the partial pressure of the inhalant vapor inhaled generally
is very high and quite variable over time, as people intermittently sniff from
balloons or from rags or bags saturated with liquid. With these high
concentrations in the inspired air, effects on the brain are almost immediate.
Because physical activity increases cardiac output, it is likely that inhalant
distribution to the brain in someone who is active will be markedly greater than
in someone at rest. Inhalants easily cross the placenta and expose the fetus, with
consequences that will be discussed later.
The situation with aerosols is somewhat different. Aerosol propellants
typically are gases or vapors. Some of the constituents of aerosol products
actually are droplets (ie, aerosols) when inhaled, and for these forms, the rapidity
and efficiency of absorption are determined by particle size (median
aerodynamic diameter). Both the propellant and the aerosolized content may
have behavioral effects. For all practical purposes, even aerosols have an almost
immediate onset of action. Thus, it is common for people who use inhalants to
breathe the gas or vapor and instantly stumble or fall down, posing a risk to
themselves and others.
It is likely that, for many use situations with inhalants, the concentrations in
inspired air exceed concentrations that would be lethal if the person were to be
exposed continuously. Lethal concentrations could occur, for example, if a
person became unconscious while still exposed to the inhalant. This situation is
probably the most common form of acute overdose. It happens when someone
using a rag or a bag laden with solvent falls in such a way as to continue
breathing the solvent. Also, some people have devised methods for exposing
themselves to inhalants without having to use their hands, such as for use in
sexual situations, and become vulnerable to overdose while using the devices.
Elimination of inhalants is very rapid once the source is removed from the
inspired air. For most of these chemicals, expired air is the major route of
elimination. Those that are relatively insoluble in the blood and brain are
eliminated more quickly than those with greater solubility in these reservoirs (eg,
toluene).
Most inhalants are metabolized to some extent, but this metabolism probably
plays a greater role in determining their hepatic toxicity than their CNS effects.
In addition, urinary phenol has been proposed as a marker for unhealthy use of
benzene and urinary hippuric acid as a marker for unhealthy use of toluene (21).
An important factor affecting recovery is the duration of the use episode.
Someone who has been inhaling for a few hours might achieve considerable
accumulation in the muscle, skin, and fat. For obese individuals, recovery can be
a bit more prolonged, as the chemicals are more slowly relocated.
Intoxication with inhalants is of shorter duration than with other substances,
with the result that many healthcare providers, as well as friends and family,
rarely see gross inhalant intoxication. Unless comatose, such people typically are
not brought to emergency departments because they will have recovered before
they get there. Law enforcement personnel occasionally encounter inhalant
intoxication if they arrive while the person is actively still using an inhalant, but
there is little they can do, even in cases of driving under the influence, because
of the rapid recovery time. Perhaps, it is this lack of direct experience with
intoxication and the difficulty of obtaining confirming clinical chemistry that has
contributed to an underappreciation of the adverse public health effects of this
form of substance use.
PHARMACODYNAMICS
The neuropharmacological mechanisms by which inhalant intoxication occurs
are poorly understood. Once inhaled, solvents rapidly enter the brain and
distribute to lipid-containing membranes within the CNS, placing them in
proximity to key functional components. Although it is presumed that the
inhalants disrupt normal neural function, it is not clear which systems are most
affected and the mechanism by which such disruption occurs. Even the question
of whether specific receptors are affected by these agents remains unresolved.
Because of the properties that solvents share with alcohol, it is logical to turn
to new discoveries about the mechanisms for the unhealthy use-related effects of
ethanol for hypotheses about how solvents might act in the brain. Currently,
evidence is accumulating that ethanol and solvents can have effects at certain
ligand-gated and other ion channel receptors, including those for gamma-
aminobutyric acid (GABAA), glutamate, and acetylcholine (8). The best current
evidence is that acute solvent intoxication is probably associated with
enhancement of GABAA and antagonism at the N-methyl-D-aspartate (NMDA)
receptors (22–24). Of particular interest is the discovery that these effects can be
very selective for different structural subtypes of these heteromeric proteins,
with different chemicals having somewhat different profiles of selectivity.
Nevertheless, definitive knowledge about the cellular mechanisms for the
unhealthy use of inhalants lags far behind our knowledge of most other classes
of drugs.
Although scientific evidence would support the view that most of the
chemicals in this class of inhalants produce alcohol- and depressant drug-like
effects, published descriptions include a much wider array of potential subjective
and pharmacological effects, including hallucinations, tremor, and seizures (25).
Certainly, some vapors can have excitatory effects in animals (such as flurothyl);
and animal studies provide some evidence that even aromatic hydrocarbons like
benzene or the isoparaffins can produce a different profile of acute effects than
the prototypic depressant solvents such as toluene (26,27). Considering how
many commercial products containing very complex mixtures are inhaled, it
should not be surprising that people who use inhalants experience a diverse array
of acute effects, depending on the product used.
ADDICTION LIABILITY
All of the vapors that have been tested produce clear, reversible, drug-like
behavioral effects in animal studies (10). In addition, self-administration studies
in rodents (28) and humans (5) have shown toluene and nitrous oxide to have
reinforcing properties. Toluene also produces a conditioned place preference in
rats and mice (29,30). When given repeatedly to animals, many drugs with
addiction liability produce sensitization to their locomotor stimulant effects, a
phenomenon thought to reflect engagement of addiction-related processes in the
brain. Trichloroethane has been shown to produce locomotor sensitization in
mice (31), and repeated toluene exposure in rats produces cross-sensitization to
cocaine and increased cocaine-produced dopamine release (31,32). Indeed,
toluene itself has been shown to enhance dopaminergic function in various
portions of the brain reward system (33,34), suggesting that there may be a
common neural basis for unhealthy use of inhalants and other well-studied drugs
with addiction liability.
Tolerance and Dependence

Little is known about the development of tolerance and physical dependence
with inhalants, but in general, they do not appear to be prominent features. It
may be useful first to describe what has been learned from carefully controlled
animal studies of tolerance and physical dependence, in which exposure
conditions are easily manipulated. Under conditions in which many drugs with
addiction liability show considerable tolerance development when given
repeatedly, inhalants do not readily produce a significant degree of tolerance to
their behavioral effects (35). It has also been difficult to demonstrate cross-
tolerance with other depressant drugs such as alcohol and the sedative–
hypnotics. This fact is somewhat surprising because animal models for tolerance
to ethanol are readily established. However, with continuous exposure (such as
that achieved with mice in inhalation exposure chambers), a mild withdrawal
syndrome can be observed with TCE (36); other vapors have not been
systematically studied. The withdrawal effects appear within hours after
discontinuation of exposure and can be considered excitatory in nature. Ethanol
and barbiturates can suppress these withdrawal signs, suggesting a cross-
dependence between inhalants and CNS depressants.
Unhealthy inhalant use typically is episodic in nature and thus generally
would not occur with sufficient frequency and intensity to maintain a constant
exposure throughout a day, much less the weeks or months it might take for
physical dependence to develop. Thus, it is not surprising that significant
physical dependence on inhalants is rarely seen, if at all, in clinical settings.
On the other hand, several studies find that people who use inhalants report
withdrawal signs associated with inhalant use (37,38), but this may not represent
a true abstinence syndrome so much as a manifestation of toxicity. There is little
evidence of the use of inhalants to avoid a withdrawal syndrome, and a
characteristic withdrawal syndrome is not included in either the DSM-IV or
DSM-5 inhalant use disorder criteria sets. However, people who regularly use
inhalants clearly can develop a pattern of uncontrolled use, marked by a
devotion of considerable time and efforts to obtaining and using inhalants that
are characteristic of an SUD.
Clinical Chemistry
Although few, if any, clinical facilities will routinely conduct tests for the
presence of inhalants; such tests can be ordered through special services
provided by commercial laboratories. Typically, these tests are performed using
blood or urine and appear to be available mainly for solvents such as toluene,
benzene, and methyl ethyl ketone. Because inhalants are eliminated so rapidly
after acute exposure, such tests would be expected to have a high probability of
producing false negatives. Nevertheless, technological advances can be expected
in this area (21). Problems associated with postmortem detection of volatile
solvents have also been described (39).
TOXICITY/ADVERSE EFFECTS
It is difficult to summarize what is known and not known about the adverse
consequences of unhealthy inhalant use. The discussion that follows focuses
almost exclusively on the subclass of inhaled solvents, fuels, and anesthetics.
Their toxicity differs depending on which of this broad array of chemicals and
chemical mixtures is being used. The toxicology of commonly used solvents is
reviewed in reference texts (40), which can be consulted for specific information
on compounds of interest. A brief overview of the information is provided here.
Nitrous oxide will be mentioned when appropriate, but the situation with alkyl
nitrites is probably very different. The known side effects of organic nitrites used
for smooth muscle relaxation would be relevant to unhealthy use of these
compounds, but a systematic study of the health consequences in people with
nitrite use disorder has not been done.
Acute Effects
Deaths related to the acute effects of inhalants are well documented (41–43).
There are two primary sources: behavioral toxicity and overdose. Because the
solvent class of inhalants can produce profound intoxication and even anesthetic-
like effects at high concentrations, it would not be surprising for accidents and
injuries related to behavioral toxicity to occur. Vulnerability to these events
probably is enhanced by the rapid onset of intoxication. Additive effects would
be expected when these inhalants are used in combination with alcohol or other
CNS depressant drugs. Overdose occurs when people lose consciousness while
being continually exposed to the inhalant, allowing lethal concentrations to
accumulate in the brain. As with anesthetic vapors, the concentration–effect
curves for inhalants are very steep, with toxic exposures achieved easily under
the poorly regulated exposure conditions of actual use.
It appears that the proximate cause of most overdose deaths is CNS
depression, leading to respiratory problems or suffocation. Treatment of
overdose rarely occurs in emergency departments because victims usually are
either dead or recovered by the time they arrive. In addition to these overdose
situations, at least some of the inhalants appear capable of producing acute
cardiotoxicity, even in otherwise healthy young people. The mechanism may be
increased sensitivity of the myocardium to circulating catecholamines, which
may occur when an intoxicated individual engages in some strenuous activity.
This phenomenon has been termed “sudden sniffing death” and has been
associated particularly with the abuse of aerosols containing chlorofluorocarbon
and butane propellants and refrigerants that contain them. The contribution of
hypoxia to the acute toxicity of inhalants should be considered, especially with
the use of nitrous oxide, in which even 100% concentrations are not lethal except
for the loss of oxygen.
Chronic Toxicity
Because of the diverse array of chemicals subject to unhealthy inhalant use, it is
difficult to summarize their chronic toxicity. The situation is made even more
complicated by the fact that few people who use inhalants chronically confine
themselves to a single product or a single chemical agent. Add to this the fact
that many of these commercial products are complex mixtures, and it becomes
difficult for a toxicologist to ascertain the specific etiology of any adverse health
effects seen in people who use inhalants. Some adverse effects may be secondary
to inhalant exposure or reflect lifestyles. These may include such known
predictors of poor health as homelessness, inadequate diet, and other substance
use. Thus, data from case reports in inhalant use situations always should be
viewed cautiously. Careful epidemiological work that controls for key covariants
in this population has yet to be done.
In animal studies, it is easier to study individual chemicals, but research in
this area typically has been done to simulate the long duration and low
concentration exposures that might be experienced in the home or workplace.
Few studies attempt to model the repeated high concentration and intermittent
exposure most typical of people who use inhalants. Many people who use
chronically manifest adverse health effects, some of which can be used in
diagnosing the problem. Common target organs are the nose and mouth area,
lungs, brain, liver, and kidney. There also are physical dangers in using highly
inflammable and explosive chemicals.
Neurotoxicity
Many, if not all, inhalants can be neurotoxic and some components of these
products are well-characterized neurotoxicants. Among these are hexane and
methyl-n-butyl ketone, which produce axonopathies. The lead in leaded gasoline
(still used in many countries throughout the world) produces classic
demyelination. Other commonly used chemicals (such as toluene, the
haloalkanes, and propane) have less well-described chronic effects on the brain
and behavior. Human neural imaging studies and clinical observations suggest
that they can produce neurotoxic effects at high exposures, but systematic
studies with proper controls are lacking. Most of the information on
neurotoxicity of inhalants comes from case reports or small series of patients. It
is not known what percentage of people have detectable brain damage nor
whether the inhalants alone were responsible for the observed effects. Brain
scanning, neurological and neuropsychological assessment, or autopsy reports of
people who use inhalants show many types of neuropathologies, including loss
of white matter, brain atrophy, and damage to specific neural pathways (44–46).
Of particular concern are the effects of inhalants on the developing nervous
system where animal studies have revealed evidence for developmental delays
(47,48) and reversible changes in white matter maturation (49), suggesting that
the prenatal period through adolescence may be particularly vulnerable periods
for inhalant exposures. There are a few case reports of Guillain-Barre syndrome
in people who use nitrous oxide.
Psychiatric Disorders
The association of early inhalant use with increased risk of many SUDs has been
described. For example, Wu and Howard (50) reported a very high rate of
psychiatric disorders among people who use inhalants in the general US
population. For example, 70% of people who use inhalants in this sample met
the criteria for at least one lifetime mood, anxiety, or personality disorder and
38% experienced a mood or anxiety disorder in the past year. Females were
more likely than males to have multiple comorbid psychiatric illness. Conduct
disorder, mood disorders, and suicidality are common among adolescents who
use inhalants (51–53).
Effects on Major Organ Systems

Many people who use solvents chronically develop irritation of the eyes, nose,
and mouth and exhibit rhinitis, nose bleeding, conjunctivitis, and a localized skin
rash. When these signs are accompanied by the odor of solvents on the breath or
in clothing; by paint, adhesive, or other similar stains on clothing; or by
possession of products in unusual circumstances or amounts, inhalant use should
be suspected. With chronic use, inflammation of the lungs can result in coughing
and may compromise respiration, and bone mass toxicity has been reported.
The liver is an important target in chronic exposure to many solvents,
particularly those that undergo some metabolism. Of particular concern are some
of the halogenated hydrocarbons, such as carbon tetrachloride. It could be
speculated that persons with other types of liver disease, such as hepatitis or
alcoholism, would be particularly vulnerable. Kidney damage also has been
reported, in the form of glomerulonephritis and kidney stones. There have been
reports of renal tubular acidosis in acute toluene intoxication (54). Benzene and
vinyl chloride are known carcinogens. Nitrites and methylene chloride can
produce methemoglobinemia.
Fetal Solvent Syndrome

It has been estimated that as many as 12 000 women use inhalants while
pregnant in the United States alone. The research on inhalant use and pregnancy
(47) suggests that decreased fertility and spontaneous abortions in some women
may be related to inhalant use. Clinical reports of adverse effects in the offspring
of mothers who use solvents include low birth weight, facial and other physical
abnormalities, microcephaly, and delayed neurological and physical maturation.
Because certain features seen in these children resemble the fetal alcohol
syndrome, a “fetal solvent syndrome” has been proposed. Whether these features
result from direct teratological effects of the chemicals or some lifestyle
covariants associated with solvent use is unknown at this time. Nevertheless,
confirmation of adverse effects of prenatal solvent exposure has been obtained in
animal studies (47,48). Thus, clinicians should be alert to this possibility in
patients who use inhalants during pregnancy.
FUTURE RESEARCH DIRECTIONS

Inhalant use is one of the least understood substance-related problems. This is
primarily related to the fact that there has been little research in this area (55),
generally because of mistaken beliefs about inhalant use that even exist within
the scientific community. These beliefs include the ideas that (a) inhalant use is a
transient phenomenon of adolescence that has relatively little associated
morbidity and mortality, (b) inhalants have “nonspecific effects” on the brain
and behavior that do not lend themselves to the study with modern technologies
in behavioral and molecular neurobiology, (c) laboratory studies of vapors and
gases are very difficult to perform, and (d) there are too many chemicals to
successfully sort out the similarities and differences in terms of their addiction
potential and toxicity.
Our understanding should improve with the increasing information available
from animal models (8). However, there are some unique problems inherent in
the study of inhalant use. The most significant is that it will be difficult to
conduct laboratory-based human exposure studies of many of these compounds
at behaviorally active concentrations. Such studies have been very important
with other substances. One approach to overcoming this problem may be to draw
lessons about the effects of chemicals of this type by studying the medical use of
general anesthetics. This approach has been used successfully by Zacny and
colleagues (4,5). It is particularly useful in studying nitrous oxide. Animal
studies of inhalants will be especially important because there are fewer
limitations on the exposure conditions.
We need a lot more information on the phenomenology and adverse health
and social consequences of acute inhalant intoxication, some of which could be
obtained from prospective longitudinal studies of inhalant use (56).
Epidemiological studies are made difficult by the numerous types of products
and chemicals subject to inhalant use and by the fact that subclassifications have
differed from study to study. There has been an increased appreciation that alkyl
nitrite use differs from the rest, and this difference is reflected in separate
analyses of prevalence data in many reports. The U.S. National Survey on Drug
Use and Health now contains a breakdown of specific subtypes of inhalant
products, which should be useful for analyses, although it may complicate
comparing prevalence figures from one survey to another. Such progress should
lead to a better understanding of inhalant use and improved treatment and
prevention strategies.
Although it seems clear that chronic use of inhalants can cause damage to
the brain and other organs, much more information is needed about the patterns
of use that produce such effects and whether the chemicals themselves cause the
damage or whether inhalant use interacts with other factors to produce the
observed effects in some people. Considering the very large number of persons
who have experimented with inhalants, it seems certain that only a fraction of
these experience organ damage. Much more data are needed on the etiological
factors in observed cases of organ toxicity from inhalant use, and more general
population studies with appropriate control groups are needed to assess the
incidence of these effects.
Very little is known about effective treatment strategies for inhalant use
disorder. Indeed, a recent Cochrane review concludes that no data exist to form a
recommendation (57). Since most people who use inhalants are adolescents, they
are usually treated within the context of general adolescent SUD treatment
programs, often those targeting conduct disorder problems. Nonetheless, more
advice from experienced clinicians and controlled studies are needed to fill this
information gap.
CASE FOR CONSIDERATION

The parents of a 14-year-old boy report that they are concerned about
behavioral changes they see taking place in their child. The boy often spends
several hours a day after school in the garage, sometimes with friends and
sometimes alone. He and his friends have stacked up boxes to sit on, but no
obvious recreational activities are available in the garage. He does not spend as
much time with the family, sleeps more, eats less, and has been more
argumentative and more irritated. His school performance had deteriorated.
Although the boy sometimes returned from the garage slightly intoxicated, a
search of the garage and his room revealed no evidence of alcohol or other drug
paraphernalia. The boy denied drinking alcohol or smoking cannabis. The
mother becomes especially concerned when she noticed that her son had red
eyes and sores around his mouth. The parents were advised to bring their son to
see the family physician for assessment. They make an appointment, but before
the date for the physician visit, they found their son comatose in the garage. He
had fallen with his face into a paint rag that had obviously been soaked with the
fluid from an open can of paint thinner that was stored in the garage. The
garage had a strong chemical smell. They opened the garage door, moved the
boy outside, and called 911, but before the emergency response vehicle arrived,
the boy recovered consciousness, displaying slurred speech and signs similar to
alcohol intoxication. After a discussion with the family physician, the family
arranged for their son to see a psychologist experienced in adolescent conduct
disorder and SUDs.
ACKNOWLEDGMENT
Keith Shelton provided helpful comments on the initial draft of this chapter.
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SUGGESTED READINGS
58. Balster RL, Cruz SL, Howard MO, et al. Classification of abused inhalants. Addiction. 2009;104:878-
882.
60. Bowen SE. Two serious and challenging medical complications associated with volatile substance
misuse: sudden sniffing death and fetal solvent syndrome. Subst Use Misuse. 2011;46(Suppl 1):68-72.
59. Bowen SE, Batis JC, Paez-Martinez N, Cruz SL. The last decade of solvent research in animal
models of abuse: mechanistic and behavioral studies. Neurotoxicol Teratol. 2006;28:636-647.
61. Dell CA, Gust SW, MacLean S. Global issues in volatile substance misuse. Subst Use Misuse.
2011;46(Suppl 1):1-7. (Note: the entire issue of this journal is devoted to international inhalant abuse
research.)
62. Garland EL, Howard MO. Volatile substance misuse: clinical considerations,
neuropsychopharmacology and potential role of pharmacotherapy in management. CNS Drugs.
2012;26:927-935.
63. Howard MO, Bowen SE, Garland EL, et al. Inhalant use and inhalant use disorders in the United
States. Addict Sci Clin Prac. 2011;6:18-31.
64. Ridenour TA, Halliburton AE, Bray BC. Does DSM-5 nomenclature for inhalant use disorder
improve upon DSM-IV? Psychol Addict Behav. 2015;29:211-216.
CHAPTER 19
The Pharmacology of Anabolic–
Androgenic Steroids
Scott E. Lukas
CHAPTER OUTLINE
Introduction
Drugs in the Class
Therapeutic Use and Unhealthy Use
Adverse Effects
Addiction Liability
Absorption and Metabolism
Future Vistas
INTRODUCTION
Within the addiction field, the term steroids defines those compounds that
possess anabolic or tissue-building effects, but because most also have some
androgenic properties, they are more appropriately called anabolic–androgenic
steroids (AAS). This profile of effects distinguishes them from the
corticosteroids and the female gonadotrophic hormones, neither of which is
typically subject to unhealthy use. There is a rather long list of AAS that have
been produced for both human and veterinary use, and the major source of illicit
steroids is diversion from licit manufacture and distribution, as clandestine
laboratory synthesis of these products is rare. The major distinction between use
and unhealthy use is that the latter typically takes supraphysiological doses of
these compounds to increase muscle growth and enhance performance. It is the
consequence of these extremely high doses that results in serious and not always
reversible, psychiatric and medical side effects.
DRUGS IN THE CLASS

The prototypic hormone, testosterone, is the standard to which all synthetic
products are compared, and it is one of four structurally distinct groups of AAS.
The other three groups are 17α-alkylated derivatives of testosterone, 17β-
esterified derivatives of testosterone, and modified ring structure analogues (1).
The history of how testosterone and its effects on male sexual development and
tissue building were discovered is well detailed by Kochakian (2). Although
hormonal involvement in male sexual development was known in 1849, it was
not until 1930 when androsterone (a metabolite of testosterone) was isolated
from human urine. In the 1940s, after chemists had succeeded in synthesizing
testosterone, their efforts were directed toward separating its anabolic from its
androgenic effects and to make a formulation that could be taken orally. The
androgenic component of these synthetics has never been completely separated
from the anabolic effects; only the relative percentage of the two has been
manipulated. Commercially prepared products were used briefly during World
War II to promote wound healing. In 1939, Boje (3) postulated that AAS might
not only increase muscle mass but improve physical performance as well.
Hartgens and Kuipers (4) provide a comprehensive review of the pharmacology
and toxicity of AAS in athletes.
The introduction of AAS to the United States has been traced to the 1954
World Weightlifting Championships in Vienna, when the Soviet Union’s coach
informed the US coach that his team members were taking testosterone (5). In
the ensuing years, use of AAS by elite weight lifters, power lifters, and
bodybuilders increased. Over the years, their use spread to many professional
sports, especially those in which strength and body weight were important for
success (eg, football). Testosterone was the drug of choice in the 1950s, which
was replaced by more elegant synthetic compounds over the next three decades,
primarily because of their slightly higher percent of anabolic versus androgenic
effects and their relative resistance to detection by current laboratory tests. Use
spread to collegiate and amateur athletes as evidenced by the 50% positive tests
obtained by the International Olympic Committee during unannounced urine
screens in 1984 and 1985 (6). The 1990s saw a return to the use of testosterone,
which is thought to be due to improved gas chromatographic methods of
detecting the synthetic compounds and the continued difficulty of accurately
detecting exogenously administered testosterone (7). However, another trend
toward using other types of performance-enhancing aids has evolved in the wake
of pure AAS abuse.
It often is difficult to determine whether the attraction of the drugs is related
to any beneficial effect on the individual’s performance, because the drugs rarely
are taken in the absence of a training program that includes exercise and sound
nutrition (8). This concept punctuates the second aspect of AAS unhealthy use
among athletes—it usually occurs during training periods, which typically can
begin weeks and even months before a competitive event or season. The need for
these drugs by most athletes decreases during actual competition, and so the
active use can decline. However, with the advent of mandatory urine testing at
major athletic events, the risk of being caught also curtails use. Positive urine
screens that are collected during the actual competitive event are usually due to
the high sensitivity of the analytic methods to detect small amounts of
metabolites that have persisted long since use of the AAS has ceased. Once a gas
chromatographic test for hair samples had been validated, the ability to detect
AAS among athletes increased (9), and with more recent advances in mass
spectrometry and bioassays (10), the levels of detectability have decreased even
to the picogram range, which could even pick up passive exposure (11). Despite
the enhanced methods of detecting these complex compounds, controversial use
of AAS has tainted a large number of sporting events including Major League
Baseball, track and field, and professional cycling—some of these have led to
congressional investigations, and elite athletes continue to be stripped of their
titles because of discovered use. And in one case where such use was found to be
so widespread—as in the Tour de France—no winner was declared for a number
of years.
New-Generation “Performance Enhancers”

With the availability of more sophisticated urine testing procedures, the
likelihood that an athlete can avoid being caught using AAS is decreasing
somewhat, and the advent of detecting drugs like erythropoietin has contributed
to the identification of a widespread use of this performance enhancer in
professional cycling. Nevertheless, the desire for new-generation performance-
enhancing drugs and nutritional supplements continues to grow. Moreover, many
of these agents have been extremely difficult to detect using standard laboratory
procedures, not because the technology is limited but because these substances
are found naturally in the body (12), and so carbon isotope mass spectrometry is
needed (13). These include other hormones such as human growth hormone
(somatotropin), dehydroepiandrosterone, erythropoietin, and thyroxine. Cadaver
pituitary growth hormone has been replaced by recombinant human growth
hormone, and the latter has been found to increase strength and peak power
output, and fat-free mass index decreased after only a short course of the
recombinant hormone (14).
Drugs belonging to other pharmacological classes continue to be popular as
potential agents to “boost” performance. These include the mixed
agonist/antagonist opioids such as butorphanol and nalbuphine; the beta-
adrenergic agonist clenbuterol; “hormone helpers” such as gamma
hydroxybutyrate, clonidine, and human chorionic gonadotropin; and testosterone
stimulants such as clomiphene and human chorionic gonadotropin. In addition, a
variety of diuretics (acetazolamide, furosemide, spironolactone, and triamterene)
are used to help clear the AAS and their metabolites from the urine before drug
testing. Knowledge of these drugs, where to get them, doses of use, and even
recipes for adding them to training programs can be found in a number of
“underground” guides as well as from a variety of websites. In fact, a growing
concern is that many individuals have now turned to the Web as a major source
for purchasing these agents, and it appears that there are hundreds of thousands
of sites offering underground information on how to use them (15) and even
offering to sell AAS outright (16); clinicians are well advised to be aware of
these practices because the sites are often very “pro” drug use and question the
knowledge or authority of those in the medical field. The accuracy of many of
the claims on these sites is dubious at best (Table 19-1).
TABLE 19-1 List of Trade Names, Chemical Names,

and Brief Summary of the Use of the More Common
AAS Compounds
It is not just the novel drugs that are of interest, but persons with substance use
disorder continue to seek out veterinary or animal husbandry products. For
example, trenbolone is an AAS that is often used to increase muscle
growth/meat production in cattle (17) and is usually delivered via an implant into
the cow’s ear. In their paper on Web-based AAS information, Brennan et al. (15)
noted that there were many sites that described how to remove the estrogens
from this formulation, rendering it more suitable for human bodybuilding
purposes.
At-Risk Populations
It is now well established that athletes are not the only individuals to use AAS in
unhealthy ways. Unhealthy use has now appeared in adult nonathletes and even
in young boys who may be using them to simply improve their appearance (18).
Women are also using these drugs, but all estimates indicate that the percentage
remains much lower than in males. These factors encouraged the U.S. Congress
to enact the Anabolic Steroids Control Act, which effectively placed all of these
compounds, including testosterone and its many analogues, in Schedule III of
the federal Controlled Substances Act (states, of course, have the option of
scheduling these drugs even more restrictively under state law). Schedule III
includes opioids such as nalorphine, stimulants such as benzphetamine, and
depressants such as butabarbital and thiopental.
The 1990s was rife with a number of surveys demonstrating that the
incidence of AAS use and unhealthy use by adults and adolescents was lower
than that of other drugs (19,20). The data suggested that AAS were used by <2%
of the adolescents surveyed and <1% of older respondents. During the ensuing
5-6 years, new data revealed some concerning trends in AAS use, particularly
among the youth. Use among boys in general was reported to be >3% (21), and
in certain populations of 15- to 19-year-old boys, nearly 10% reported using
AAS (22). In a cross-sectional assessment using the 2003 Centers for Disease
Control and Prevention National School-Based Youth Risk Behavior Survey
database (23), Elliot et al. (24) reported that 5.3% of the 7544 females in grades
9-12 used AAS. In addition, these young women also engaged in a number of
other unhealthy life choices including using tobacco, marijuana, and diet pills,
carrying weapons, and having sexual relations before the age of 13. These
authors also noted that AAS-using females were less likely to participate in team
sports; this fuels the belief that children and adolescents have poor body image
(25). This rate of AAS use among females punctuates the twofold to fourfold
increase in AAS use that was reported by Yesalis et al. (26) in the 1990s.
However, steroid use appears to decline with age, and desire to weigh more was
a strong predictor of AAS use by males, but females who use AAS were more
likely to have higher body mass indices and a poorer knowledge of nutrition
(27). Another complicating factor in obtaining accurate information about AAS
use in teenage girls is that surveys may contain imprecise language so that the
term steroid is misinterpreted (28), leading to an inflated estimate of AAS use.
Nevertheless, the recent report of the Monitoring the Future national survey (29)
notes that annual androstenedione prevalence rates are higher than that of
steroids and that use of the former alone for 8th, 10th, and 12th grade boys is
about 0.4%, 0.6% and 0.3%, respectively, which is much lower than the rates of
0.7%, 1.3%, and 2.5% reported in 2009. The rates of using androstenedione by
girls were 0.1%-0.3%, also representing a drop in use. Unfortunately, questions
regarding “perceived risk” and “disapproval” of AAS were asked for only a few
years. Peak perceptions of risk occurred in 1993 and have steadily dropped with
a rather large plummet in 1998 and 2000. In general, when perceived risk drops
such as when public events surrounding use by famous athletes (especially
androstenedione) become widespread, use increases, and this may account for
the relatively higher use of this testosterone or other products. Perceived risk has
only slightly increased in the past years, but disapproval rates have remained
high for some years, which shows that it can be dissociated from perceived risk.
The low rates among girls are consistent among the various surveys, but these
may have limitations due to bias of both under- and overreporting between
women and men (30). This review also noted that there are significant sex-
related differences in the effects of AAS (eg, on aggressive behavior, anxiety
symptoms, and polydrug use) but that they are poorly characterized because of
the low inclusion of women in surveys or female subjects in animal studies.
While use among the lay public remains low, the incidence of use among
individuals engaged in power sports and/or weight lifting can be 20% to more
than 50% (31,32). Furthermore, there is a clear impact of the media, peer
pressure, and teasing/comments from parents as factors that predict or at least
facilitate AAS use among young boys. Numerous studies (33–35) reported that
gaming, magazines, and the media and its portrayal of sports and image about
male physical characteristics increase drive for muscularity. Indeed, in a Web-
based survey of 500 people who use AAS, 78% were noncompetitive
bodybuilders and not otherwise engaged in athletic events (36). However, very
recent data suggest that depressive symptoms and victimization are two
unexpected pathways to AAS use among adolescent boys because these factors
enhance the impact of self-perceived underweight body image (37) but that there
is also a significant risk factor for boys who perceive themselves to be either
overweight or underweight (38). Furthermore, a 2017 report revealed that sexual
orientation and race/ethnicity may play a role in the misuse of AAS with a
greater impact on Black and Hispanic adolescent boys (39). Lifetime use of AAS
has been difficult to track, but a recent analysis of multiple surveys revealed that
AAS use begins later than most other drugs with only 22% starting before the
age of 20 (40). After applying an age of onset analysis, these authors estimated
that among 13- to 50-year-olds, between 2.9 and 4 million of Americans have
used AAS and roughly 1 million may have experienced DSM-defined steroid
dependence, which is surprisingly high.
Web-based surveys have another role as revealing potential indicators of
future AAS use, based on current drug use patterns. Dunn et al. (41) reported
that 80% of respondents to the survey said that they used sports supplements
such as vitamins and protein supplements. The authors suggest that the
widespread use of sports supplements may in some way remove “barriers” for
the future use of AAS. The sample also reported a high incidence (52%) of illicit
drugs, which challenges the preconceived notion that people who use AAS are a
health conscious group as a whole and rarely engaged in other drug use. This is
apparently not the case as it has been shown that AAS use is positively
correlated with the use of other licit and illicit drugs such as alcohol, cocaine,
licit painkillers, methylphenidate, ketamine, and legal performance-enhancing
agents (42). As might be expected, the use of the two smoked drugs, tobacco and
cannabis, was not consistently reported in these studies. The fact that people who
use AAS are engaging in polypharmacy practices has only complicated efforts to
define and implement safe and effective treatments. In fact, a recent meta-
analysis of 50 studies published between 1985 and 2014 concluded that people
who use AAS frequently used other substances with alcohol and cannabis
leading the list, followed by cocaine, growth hormone, human chorionic
gonadotropin (hCG), amphetamine/methamphetamine, clenbuterol, ephedrine,
insulin, and thyroxine (43).
A very recent trend has been to use synthetic androgens or even “designer
steroids” in an attempt to achieve the same gains in strength, size, and
performance but within legal measures. Many of these over-the-counter
preparations having names like “prohormones,” “natural steroids,” testosterone
booster” are sold via the Internet and labeled as dietary supplements (44,45), and
because the chemical structures differ from the controlled drugs, they are not
illegal. There is concern that these synthetic androgens induce a specific form of
neurotoxicity resulting in neurodegenerative disease that is secondary to
oxidative stress and apoptosis (46). As a result, the use of nutritional
supplements by adolescent athletes has increased dramatically (eg, testosterone
precursors such as androstenedione, dehydroepiandrosterone, and
androstenediol) (47–50), and use continues in spite of repeated evidence that
small to moderate doses resulted in transient and modest increases in
testosterone and as such had no discernible effect on body composition or
performance (51–57). This dissociation between real efficacy and perceived
effects is thought to be due to a lack of knowledge about supplements so that a
comprehensive educational program might be useful in curtailing the use of
these supplements (58).
Recent studies have also been aimed at elucidating the mechanism of action
of AAS as well as identifying other risk factors. In the Syrian hamster animal
model, there is compelling evidence that adolescents are far more sensitive to the
effects of AAS than their adult counterparts (59). The AAS-treated adolescent
males had significantly higher sexual and aggressive behavior, whereas similarly
treated adults had significantly lower levels of sexual and aggressive behavior.
This model relates to the clinical condition as it is suspected that the neural
“rewiring” that occurs in males during puberty sets the tone for future aggressive
and violent tendencies (60) and that exposure to AAS during this critical time
can increase the likelihood that aggressive acts result in violent behavior. The
link between testosterone and aggressive behavior was further made by van
Bokhoven et al. (61) who reported that 16-year-old boys who had criminal
records had elevated testosterone levels than their peers and concluded that there
was a positive relationship between testosterone and proactive and reactive
aggression and self-reported delinquent behavior. This relationship has been
replicated in hamsters showing that exposure to AAS in adolescent animals
results in increased aggressive responses during exposure and enhanced anxiety-
like responding during AAS withdrawal (62). Exposure to AAS as adults failed
to alter the behavior of the hamsters, which would suggest that the aggressive
and anxiety-related responses to AAS are modulated by developmental elements.
Figure 19-1 depicts some of the more commonly identified effects and side
effects of AAS use in adolescents. High-dose AAS use during adolescence has
the potential of causing significantly more problems when adulthood is reached
(63). Some of the effects are easier to identify than others, so the challenge to the
clinician in detecting AAS use in his or her patients is to know the risk factors,
be able to identify the constellation of signs and symptoms of use, and ask the
correct questions when exploring use patterns (64). The clinician may need to be
vigilant when presented with requests to treat moderate to severe acne,
especially in 18- to 26-year-old males, because the incidence of acne is 50% in
people who use AAS and thus may be a clinical indicator of unhealthy use (65).
As always, the clinician must be well informed of the facts about these drugs and
be able to present themselves as a credible source of information.
Figure 19-1 Side effect profiles of AAS in male and female
persons with substance use disorder.
THERAPEUTIC USE AND UNHEALTHY

USE
Therapeutic Use
Although one might think that the therapeutic uses of AAS are of less concern to
the addiction medicine specialist, in reality, most physicians are asked to give
prescriptions for these drugs far more often than they are asked to help treat
someone who is addicted to the drugs. Thus, knowledge of these medical
situations might help in discussions with a person with a potential substance use
disorder because these individuals are likely to be aware of the medical reasons
for their prescription and may use such information in their initial attempts to
obtain legal medications to support their training or alter their appearance.
Males may receive AAS for replacement therapy when the testicles fail to
function, because of either congenital or traumatic factors, or when puberty is
delayed and short stature would result. The doses that are prescribed, however,
are much lower than those used by bodybuilders. The equivalent of 75-100 mg
per week of testosterone suffices as replacement, but weight lifters and
bodybuilders have reportedly used weekly doses of 1000-2100 mg of
methandienone (66,67). Women are occasionally treated with androgens when
metastatic breast cancer has spread to the bone. Methyltestosterone is combined
with estrogen (Premarin) to help alleviate some of the signs and symptoms of
menopause. Very recently, nandrolone has been used in combination with
exercise to increase lean body mass in patients who are on dialysis (68).
Both males and females might receive the more anabolic agents during
treatment of a rare form of hereditary angioedema. Acquired aplastic anemia and
myelofibrosis both result in deficiencies of red blood cell production, which is
combated with drugs that have equal amounts of anabolic and androgenic
effects. Sometimes, these drugs can be useful in treating the trauma associated
with burns and AIDS. Finally, just as was done in post–World War II, steroids
with more anabolic activity are useful in treating muscle wasting that is
secondary to starvation.
Unhealthy Use
AAS are used by three distinct populations: (a) athletes who use them to
improve performance, (b) aesthetes who use them solely to improve appearance
and perhaps gain some weight, and (c) the fighting elites who use them to
enhance aggression and fighting skills (59). Identifying to which of these three
populations a patient belongs to is the first step to understanding the pattern of
use and determining the best treatment plan to follow.
Athletes
Athletes use AAS for one reason: to improve their performance. Perhaps one of
the greatest mistakes a clinician makes in dealing with an athlete is attempting to
dissuade their use because the drugs cannot improve performance. In fact, this is
not true. The older research studies that purported to show that the effects of
AAS were no different than placebo suffered from a number of methodological
problems, did not control for motivation, and failed to document the amount of
physical training. In addition, ethical considerations prevented the investigators
from administering extremely high doses, which are considered necessary to
achieve the muscle-building effect. Negative findings also have been attributed
to the use of only one drug at a time in the research studies, whereas athletes in
training typically use multiple drugs in combination. The continued use of these
drugs is based on the belief that they increase muscle capacity, reduce body fat,
increase strength and endurance, and hasten recovery from injury (69). Many
athletes also believe that AAS-assisted training allows the person to increase
both the frequency and the intensity of workouts—factors that contribute to any
direct benefits of the drugs (70). A recent Web-based survey revealed that
bodybuilders and weight lifters use on average 3.1 agents, engage in cycles that
last 5-10 weeks in length, and use doses that are 5-29 times greater than
physiological replacement doses (71). Rates of use among individuals in fitness
centers are also much higher (~12.5%) than the general population (72).
In the world of professional weight lifting and bodybuilding, AAS are used
in three basic patterns: “stacking,” “pyramiding,” and “cycling.” Stacking is the
practice of using multiple products at the same time. Persons who use AAS
believe that the beneficial effects of one drug will complement those of another
and that they will only achieve real benefits through a specific combination.
There are now animal data to support the notion that stacking AAS can result in
an altered pharmacological response. Wesson and McGinnis administered a
number of combinations of testosterone, stanozolol, and nandrolone to
adolescent male rats and found that behavioral and endocrine effects were
altered. Furthermore, this simulated “stacking” procedure revealed that the level
of androgen receptor occupation did not directly correlate with the effects of the
combined agents (73). A pyramid plan involves starting with a low dose and then
gradually increasing the dose until peak levels are achieved a number of weeks
before competition. The individual then slowly decreases or tapers the drug dose
down, and because the beneficial effects of AAS persist long after their use has
been discontinued, the athlete will be primed for the competitive event. Cycling
refers to the practice of using different combinations over a period to avoid the
development of tolerance or loss of effectiveness. Thus, different combinations
of drugs are used over a 6- to 12-week period, after which another drug or
combination is substituted.
A rather poignant example of how extensive the use pattern can be is
provided in Table 4 of the review by Graham et al. (13). This table details a 16-
week profile of stacking, pyramiding, and cycling of 19 different drugs from a
half-dozen different pharmacological classes by a current UK bodybuilding
champion. The breadth of combinations, patterns, and huge doses is quite
extensive, and while this pattern appears to be on one end of the spectrum, this
practice is widespread, and the clinician will find it necessary to become familiar
with a number of different drugs (like diuretics, thyroid hormone, and insulin) as
a reminder that few individuals engage in unhealthy use of a single agent and
that other medications are used to either “boost” or facilitate the elimination of
target drugs.
When prescriptions for AAS cannot be obtained, individuals may sometimes
turn to veterinary products (as noted above). It is an interesting paradox when
young bodybuilders profess to be on strict diets and use only the purest of
vitamin and dietary supplements, yet they will self-administer drugs for which
use in humans has not been approved. Products that are not approved for use in
the United States typically are obtained by mail order from abroad. Because the
testing of these products in some other countries is not as stringent as that in the
United States, patients should be cautioned about using such products. Finally,
there is an extensive black market of AAS that supports a rather large percentage
of inactive products that are falsely advertised as containing anabolic steroids.
Aesthetes
Another group of people who use AAS is composed of young boys and girls
who use these drugs primarily to increase their weight or to improve their
physical appearance (74–77). This desire for weight gain among a group of
adolescent boys who are not yet taking AAS may place them at risk for initiating
use (76). This trend is disturbing because these authors noted that a significant
number of the boys were unaware of the most dangerous risks associated with
AAS use. A recent study of the prevalence of AAS use among 6th-12th grade
Canadians revealed that 2.8% of the respondents had used these drugs over the
past year (78). A disturbing trend was that 29.4% of these students reported that
they injected the drugs and 29.2% of these reported that they shared needles with
friends. Young AAS users are also likely to use other drugs such as marijuana,
smokeless tobacco, and cocaine (79). These authors also reported a high
percentage of needle-sharing behavior among adolescents.
In general, the doses used by adolescents and others who want to improve
their appearance are substantially lower than those used by adult athletes (80).
Further, the pattern of lower doses and intermittent cycles of use is likely to
obviate the development of major side effects. However, because young boys are
often still in transition because of hormonal changes associated with puberty,
these drugs can have other significant effects. For example, the epiphyseal plate
of the femur can close prematurely and stunt a boy’s growth (81), which is
contrary to what a significant number of adolescents believe. More importantly,
these young people who use AAS may be particularly sensitive to the increased
aggressive effects resulting from their use (80).
Apparently, a substantial proportion of these adolescents are also unaware of
the side effects of AAS. Although educational programs have been slow to
incorporate these drugs in the lesson plans, the real reason that the public is so
unaware of the risks is that these drugs are probably not a severe health hazard
when taken intermittently and in low to moderate doses (80). Because programs
that simply emphasize the negative aspects of drugs are ineffectual at curtailing
use (82), the health professional should balance the discussion about unhealthy
AAS use with the straight facts and not try to overstate the degree of harm. Such
actions will only alienate the patient. Unfortunately, these young people know
that only a small percentage of people who use AAS will experience very
serious and deadly outcomes and that it will not happen to them. For the others,
the side effects (except for some effects in women) are largely reversible.
Fighting Elite
Very little is known about this population of AAS users. This profile was
originally described by Brower (83) and includes individuals who seek to
increase their strength in order to perform their job. Another desired effect is the
increase in aggressiveness that may also help them with their jobs. Thus,
bouncers at bars, security personnel, and even law enforcement officers (84,85)
have been reported to take these drugs.
Personality Profiles
A study of the personalities of people who use AAS by Cooper et al. (86)
identified a high rate of abnormal personality traits in a sample of 12
bodybuilders who used AAS compared with a matched group who did not.
Along with being heavier than the controls, the people who use AAS were more
likely to score higher on measures of paranoia, schizoid, antisocial, borderline,
histrionic, narcissistic, and passive–aggressive personality profiles. Further, the
incidence of abnormal personality traits before AAS use began was not different
from the control group, suggesting that such disturbances are secondary to their
use. People who use AAS also reported that they believe that AAS not only
enhance physical strength and athletic ability but increase confidence,
assertiveness, feelings of sexuality, and optimism (87). There appears to be both
a pathological perception of body image and a very narrow (stereotypic) view of
what a male body should look like among AAS users (88). The term reverse
anorexia nervosa has been coined by this group to describe symptoms
association with muscle dysmorphia or a pathological preoccupation with
muscularity (eg, not willing to let their bodies be seen in public). This particular
form of body dysmorphic disorder may be associated with psychopathology as
evidenced by a greater incidence of suicide attempts, higher frequency of
unhealthy substance use, and poorer quality of life (89).
ADVERSE EFFECTS
Pope et al. (90) have pointed out that the common belief that performance-
enhancing drugs are fundamentally safe has led to their continued use, especially
among the nonathlete weightlifter community. The dangers of
supraphysiological doses of these drugs preclude the conduct of randomized
controlled studies with humans, and so observational studies have remained the
major source of knowledge. This review (90) provides a comprehensive
overview of the adverse effects that have been associated with a number of
different agents. As a result of the many observational studies, a great deal is
known about the side effect and toxic profile of these drugs, and in the last few
years, an even better appreciation for the risks of using these drugs has occurred.
Much of the recent literature has focused on the short-term toxicity of these
agents, particularly on cardiovascular and hepatic function. However, since
people who use AAS rarely seek treatment for their unhealthy use of these drugs,
they will present with just the side effects and may not reveal their history of
high-dose AAS use. One important consequence to consider is that as AAS users
age, their use may subside, but potentially long-lasting organ damage may have
occurred that may accelerate the deterioration that occurs during the normal
aging process. As unhealthy AAS use peaked in the 1980s, there is likely a
generation of older men who may begin to experience the consequences of their
past use. This issue has recently been addressed in a cross-sectional survey (91)
showing that AAS users were more likely to report concomitant alcohol use
(binge drinking) and report a higher incidence of anxiety disorders.
Side effects are generally reversible, but more serious medical consequences
and even toxic reactions appear to involve primarily blood chemistry, endocrine
function, the liver, the cardiovascular system, and the nervous system. Reports
that excessive amounts of these drugs lead to certain types of malignant cancers
have not been substantiated. Overall, even the more serious side effects have
disappeared within 3 months of discontinuing their use, yet benefits such as
increases in lean body mass and increased diameter of muscle fibers remain (92).
Although the side effect profile of AAS has been well documented in adults, less
is known about how chronic use of high doses of AAS will affect adolescents.
Administration of the 17-alkylated androgens can cause a dramatic reduction
in high-density lipoprotein (HDL) cholesterol, but because there is a nearly equal
increase in low-density lipoprotein (LDL) cholesterol, there is no net change in
total cholesterol levels (93). Other agents such as nandrolone and testosterone
esters fail to produce this profile (93,94). Although the long-term detrimental
effects of altered HDL/LDL ratios are known to predispose humans to
atherosclerosis, documented morbidity and mortality as a result of AAS use have
been rare (95,96). The lack of direct correlations may also be due to the fact that
different steroids have varied effects on lipid dynamics (94). Thus, although
people who use AAS stack different drugs to improve the beneficial effects, this
practice may actually afford some protection against these side effects. Further,
the relative paucity of coronary vascular disease in athletes who use these drugs
may also be due to the fact that other risk factors (eg, diet, exercise, low body
fat) compensate for any negative contribution afforded by the HDL/LDL profile.
Such protection, however, may not be present in individuals who use AAS just
to improve their appearance and do not engage in athletic activity. Platelet
aggregation (97) and increased red blood cell production and slight increases in
systolic blood pressure have been suggested to be important factors that increase
an individual’s risk for thromboembolic disorders (1,98).
Because testosterone exerts an inhibitory action on the hypothalamic–
pituitary axis, administration of natural or synthetic analogues of testosterone
decreases testicular size and sperm count (99,100). Residual amounts of active
metabolites may keep the levels of follicle-stimulating hormone and luteinizing
hormone low, and coupled with the relatively long cycle to produce sperm, the
recovery is likely to be slow but often is complete. Aromatization is the process
by which steroid hormones are interconverted. For example, testosterone is
converted to estradiol and estrone, and high-dose male AAS users can have
circulating estrogen levels of normally cycling women (1). These circulating
estrogens exert the usual feminizing effects, such as gynecomastia. Compounds
that resist aromatization (eg, fluoxymesterone, mesterolone, stanozolol) may not
result in the feminizing effects (101).
Although a wide variety of medical disorders (and even exercise) can
increase the amount of liver enzymes in the blood, this response is primarily
limited to the use of oral, 17-alkylated AAS. The relationship between these
drugs and elevated enzyme levels exists because these orally effective drugs are
metabolized by the liver, the first-pass effect delivers an exceptionally large
percentage of the dose to the liver, and people who use AAS typically take
excessive doses that further stress liver function. This profile often results in
cholecystic jaundice (102), but because inflammation and necrosis are not
present, the symptoms are limited to an accumulation of bile, which spills over
into the blood. Interestingly, many bodybuilders use this side effect as a metric
of their dosing regimen and titrate themselves to levels that just precipitate
jaundice (103).
Peliosis hepatitis is a disorder characterized by blood-filled cysts scattered
throughout the liver; a detailed description of the history of this disorder and its
relationship to unhealthy AAS use is presented elsewhere (104). It has been
associated with the 17-alkylated androgens, rarely results in symptoms, and
likely resolves with discontinuation (105).
The evidence linking 17-alkylated androgens with hepatic tumors is well
established. Except for the fact that the androgen-related adenomas are typically
larger, the profile resembles that of women who take birth control pills. The risk
for developing hepatocellular adenomas ranges from 1% to 3% of people who
use AAS (93), and as with peliosis hepatitis, these adenomas rarely result in
symptoms and are often not documented until a routine autopsy is performed.
A better appreciation for the mechanism of hepatic toxicity is now apparent
as prolonged AAS use appears to increase lysosomal hydrolase activity and
decrease some components of the microsomal drug-metabolizing system (106).
These macroscopic changes may very well lead to the inflammatory or
degenerative lesions in centrilobular hepatocytes, ultrastructural alterations in
canaliculi, and degenerative changes in mitochondria and lysosomes. Stanozolol,
along with the other orally administered AAS, is known to induce these effects.
Moreover, it is clear that chronic AAS use may negatively impact immune
function by overactivating immune cell function while dampening
immunological responses (107). Testosterone, at higher concentrations, reduces
extra- and intracellular superoxide and increases phagocytosis, indicating that
the oxidative capacity of neutrophils has decreased.
AAS affect the cardiovascular system via their effects on HDL/LDL ratios
and other blood products. However, there are reports that these drugs can
directly affect myocardial tissue. The majority of the evidence comes from
animal studies in which high doses of methandrostenolone result in myocyte
necrosis, cellular edema, and mitochondrial swelling (108,109). Because these
changes cannot be duplicated by exercise alone, it is likely that these effects
were responsible for the clinical case report of an AAS user who suddenly died
of cardiac arrest (110). Recent preclinical studies suggest that the combination of
vigorous exercise along with AAS use may precipitate myocardial injury that is
manifested by myocardial disarray, contraction band necrosis, interstitial
fibrosis, and apoptosis (111). These direct cardiotoxic effects can result in
hypertrophy, electrical and structural remodeling, and contractile dysfunction
that can lead to increased risk of ventricular arrhythmias and sudden cardiac
death (112). A 2013 clinical report supports the notion that AAS use (possibly in
combination with cannabis) can contribute to ischemic stroke in adolescents
(113), and a recent review of the extant clinical literature revealed a high
incidence of cardiac toxicity associated with chronic use (114). Angell et al.
(115) present two case studies (a 25-year-old bodybuilder and a 27-year-old
professional skater) that highlight the impact that performance-enhancing drugs
have on cardiovascular function, especially in athletes. Frati et al. (116) have
performed a review of the literature and have identified 19 AAS-related fatal
cases that were not cardiac related.
An adverse effect of AAS use during high-intensity training periods that is
not well documented is the incidence of injury that may occur as a direct result
of their use. Cross-sectional cohort study revealed that ruptured tendons
(especially upper body) occurred in 22% of the AAS users with a hazard ratio
for first incident being 9.0, which was highly significant (117). Although it
might seem that the fact that people who use AAS can train with these drugs
well beyond what they would be able to tolerate without the drugs is responsible
for injuries of this type, it is possible that the growth of muscle mass is not
paralleled by an increase in ligament support, which can result in such failures.
Support for this contention was supplied by Turillazzi et al. (118) who posit that
AAS-induced tolerance to exercise places muscles at risk for overload that may
shield the fibers from damage and improve recovery but that this protective
action breaks down when exercise programs are excessive.
Controversy remains over the degree and extent of the severity of AAS-
induced extreme psychiatric effects often referred to as “roid rage.” These
eruptions of frenzied violent behavior during a cycle of high-dose AAS have
been described in a few case reports, but no laboratory studies verifying such
reactions have been published. More frequently, cases in which psychiatric
effects appear associated with drug use have been reported (119–123). The
constellation of symptoms appears to most closely resemble those of hypomania
or mania. The energized user of AAS talks faster, has more energy, sleeps less,
and is being more impulsive, even to the extent of purchasing expensive cars
(122). At the far end of the spectrum, mania may lead to delusions and even
hallucinations. Interestingly, many individuals with body dysmorphic disorder
present with delusions as well (124). Two studies (125,126) attempted to
standardize the collection of these data and found that using structured
interviews, the incidence of a full affective syndrome was present in 22% of a
population of 41 bodybuilders (126). Another 12% displayed psychotic
symptoms that clearly emerged during AAS use. The cohort of 20 weight lifters
who used AAS experienced more somatic, depressive, anxious, hostile, and
paranoid complaints than those who did not use these drugs (125). A 2012
survey (127) revealed that, compared to nonusers, AAS-dependent users had a
25.9% incidence of any psychiatric illness, with the majority of the issues being
anxiety disorder (16.1%) and major depression (15.2%), which were statistically
elevated. The variables that contribute to these findings are now better
understood to be related to an earlier onset of use (as in adolescence) because
these individuals experience poorer performance on cognitive tasks and had
worse impulse control while on cycle (128). These cognitive deficits appear to
be selective for certain elements such as visuospatial memory, while leaving
response speed, sustained attention, and verbal memory intact (129). A recent
brain imaging study (130) revealed that long-term AAS users had enlarged right
amygdala with reduced connectivity that paralleled brain chemistry changes that
reflected a reduced turnover of glutamate. As the amygdala plays a role in
cognitive control and spatial memory, these changes may reflect the
neurobiological mechanisms of the psychiatric disturbances and cognitive
difficulties (129) observed in people who used AAS chronically.
Empirical evidence of drug effects on aggressive behavior has been obtained
using the Karolinska Scales of Personality (131) and a human laboratory model
of aggression, the Point Subtraction Aggression Paradigm (132). More recently,
psychiatric side effects after supraphysiological doses of combinations of AAS
were reported to correlate with severity of use (132). Results from the
personality scale indicate that a cohort of AAS users exhibits significantly more
verbal aggression, impulsiveness, and indirect aggression. Yates et al. (133)
reported that three measures of the Buss-Durkee Hostility Inventory (134),
assault, indirect aggression, and verbal aggression, were elevated in a group of
current or recent AAS users. The Point Subtraction Aggression Paradigm
directly measures the amount of provoked aggressive behavior in the laboratory
by ostensibly taking away points (that are worth money) from an individual who
believes he is playing against another person. In reality, the subject plays against
a computer program, and the experimenter actually controls the rate of
provocation. Both aggressive and nonaggressive behaviors are recorded, so the
effects of various drugs on responding per se can be viewed independent from
aggressive responding. Using this model, moderately high doses of testosterone
cypionate (600 mg, intramuscularly, once per week) can increase aggressive
responding in individuals who had not used steroids before (135). Interestingly,
animal models have confirmed that AAS administration increases aggressive
behavior (136). As weight lifters and bodybuilders have reportedly used weekly
doses that exceed three times that used in research studies, it is reasonable to
suspect that aggressive behavior can result from these training programs.
Collectively, it appears that AAS use can result in hypomania and even
psychotic symptoms, whereas depression may ensue during withdrawal. The
lack of well-controlled prospective studies has prevented a more definitive
association between AAS use and psychiatric disorders. It is unlikely that such
data will become available in the near future because ethical constraints will
preclude the conduct of any double-blind assessments of supraphysiological
doses of these drugs.
ADDICTION LIABILITY
Unhealthy AAS use includes a variety of social and psychological components
that are not easy to imitate either in animal models or in currently validated
methods of assessing addiction liability in human volunteers. The concepts of
perception, motivation, and expectation play a pivotal role in the initial use and
subsequent unhealthy use of these compounds. Because the anabolic effects of
AAS can be profound but slow to develop, it has been difficult to separate these
“desired” muscle-building effects from direct reinforcement. Demonstrating
tolerance and physical dependence on these agents has also proved to be elusive
because there are limitations in the doses that can be given to human subjects.
Reward
Although the anabolic steroid addiction hypothesis was proposed nearly 20 years
ago (137), few empirical studies have been conducted to actually test it. This has
been primarily because it is often difficult to separate the direct rewarding effects
of AAS from the ancillary positive effects on performance, weight gain, and
physical strength, which are the primary reasons that these drugs are used (138).
Therefore, animal models of conditioned place preference and self-
administration have been employed to test these relationships, and evidence is
mounting that AAS may possess some reinforcing effects that are not related to
athletic performance. There is mounting evidence that AAS have a direct impact
on the mesolimbic reward system (138) and several animal studies have
demonstrated that testosterone is reinforcing in both male rat and hamster animal
models using intracerebroventricular (icv), intravenous, or oral self-
administration (139–141).
Ballard and Wood (142) showed that hamsters preferred to self-administer
the injectable androgens nandrolone or drostanolone and failed to self-administer
orally active androgens oxymetholone or stanozolol. Even still, self-
administration of AAS drugs is modest compared to drugs like cocaine and
heroin and, as such, does not appear to be directly related to dopamine (143).
This would suggest that the AAS reward circuitry is not directly tied to this
neurotransmitter, much like that of alcohol and the benzodiazepines, even though
their use can have a modulatory role on dopamine.
Perhaps the most important concept to understand about unhealthy AAS use
is that these agents are not used in the typical patterns that are observed with
traditional drugs such as cocaine, heroin, alcohol, nicotine, and marijuana.
Indeed, AAS are often taken or injected once per week as part of an exercise
program. It is well known that if the subjective effects of a psychoactive drug are
sufficiently delayed after self-administration, then the drug’s reinforcing efficacy
decreases and drug-seeking behavior is reduced (144). Although there are a few
scattered anecdotal reports that high doses of AAS can elevate mood, no
controlled studies have demonstrated that these drugs produce immediate
positive mood effects or euphoria. AAS can act within minutes to hours on cell
membrane receptor sites, but the real beneficial effects of such action (eg,
protein synthesis) take more time. So, because of the difficulties of conducting
such studies with humans, animal models have been proven to be the most
valuable in discerning the nature of the reinforcing effects of these compounds.
In one clinical study by Su et al. (145), healthy non-AAS users described feeling
euphoric, being full of energy, and having increased sexual arousal after an acute
dose of methyltestosterone. Although the magnitude of the response was modest,
the results were consistent but have not been replicated.
The rewarding effects of testosterone using conditioned place preference
were described (146) but appeared to be dependent on the environmental cues as
conditioned stimuli. A recent study in male rats demonstrated that these drugs
may alter the sensitivity of brain reward systems (147). In that study, a 2-week
treatment with methandrostenolone alone had no effect on brain reward systems,
but a 15-week treatment with a cocktail of three different AAS resulted in a shift
in the response patterns to brain electrical reward and amphetamine. In a related
study, dopamine receptor density in nucleus accumbens was altered by
supraphysiological doses of testosterone in male rats, suggesting that dopamine
levels are increased after AAS (148). This action was verified using positron-
emission tomography and found that chronic AAS treatment caused an up-
regulation of the binding potential of dopamine in rat striatum (149).
Another potential link to potentially addictive substances is that AAS share
brain sites of action and neurotransmitter systems with opioids. In humans,
unhealthy AAS use is often associated with prescription opioid use, and in
animals, AAS overdose produces symptoms resembling opioid overdose (150).
This study also demonstrated that AAS modifies the activity of the endogenous
opioid system. A recent review by Mhillaj et al. (151) summarizes the data
suggesting that AAS dependence may arise due to an enhancement of
endogenous opioids (137), which would explain the rather large number of
studies demonstrating that AAS users are also prone to high rates of DSM-
defined opioid abuse and dependence (152,153) and that use of both classes of
drugs developed at about the same time (32).
The absence of a well-defined pattern of self-administration in animals is
confirmed by the finding that humans cannot tell whether they have been given
an active AAS or placebo (154). Marginal discriminations were made in two
studies but only after a period of extended testing had been employed (67,155).
However, it is likely that it was the side effects of these drugs that were detected,
rather than any positive reinforcing effects. Because the latter are thought to
regulate drug-taking behavior in both humans and animals, the question that
remains is “why do humans engage in unhealthy AAS use?”
Collectively, these data from animal models suggest that AAS may very well
be reinforcing, but the magnitude and strength of the direct rewarding effects of
these agents are modest at best and do not appear to approach that of the more
classic drugs such as heroin, cocaine, or nicotine. Because of testosterone’s role
in a number of socially labile situations, it may be that it intensifies the
rewarding aspects of these other behaviors and that is what contributes to the
persistent use by a small fraction of the population.
Tolerance
The evidence supporting tolerance development is not strong, although there is a
belief among people who use AAS that cycling is a necessary practice to avoid
its development. Twenty percent of a sample of weight lifters believes that
tolerance develops, but more than 80% believe that dependence (based on DSM
criteria) develops. Nevertheless, such concerns over lost efficacy with time
appear to be without hard empirical evidence. As such, it must be assumed that
the escalating doses that elite athletes use are not taken because tolerance
develops to their effects, but because it increases the magnitude of the desired
effects. The doses are increased slowly to minimize the side effects or to allow
time to acclimate to them. When presented with this fact, some people who use
AAS are likely to confuse their behavior with tolerance.
Substance Use Disorder

Although evidence of physical dependence on AAS has not been widespread,
there are a few detailed reports of clear signs of withdrawal when their use was
abruptly stopped (156–158). Using DSM criteria in a study of 49 male weight
lifters (158), 84% reported experiencing withdrawal effects, and the most
frequently reported symptoms were craving for more steroids (52%), fatigue
(43%), depressed mood state (41%), restlessness (29%), anorexia (24%),
insomnia (20%), decreased libido (20%), and headaches (20%). Interestingly,
42% of these subjects were dissatisfied with their body image during withdrawal
as well. Those who reported being addicted to AAS generally took higher doses,
completed more cycles of use, and reported more aggressive symptoms than
those who did not report being addicted. However, the extent of addiction on
AAS in the larger population of people who use AAS may be considerably
smaller as there have been no reported cases of withdrawal effects in female
athletes or among patients who have been prescribed with high doses for
legitimate medical purposes.
AAS in fact can increase muscle mass and body weight, especially when
used along with a regular training program. However, many of the “black
market” AAS preparations sold during the late 1980s were devoid of any active
ingredients, including AAS. In spite of the spread of these counterfeit drugs,
pepeople who use AAS claimed to have experienced improvements in their
performance. Herein lies the real difficulty in assessing the addiction liability of
these compounds. They are not expected to have immediate beneficial effects,
and so the delay in any improvement does not raise suspicion that the
preparation may be inert. Nevertheless, whether these drugs really do increase
muscle mass, improve performance, or increase endurance is not the question
that confronts the addiction medicine specialist. The fact that AAS-seeking
behavior exists and that extremely high doses are used over relatively long
periods suggests that there is a steroid use disorder and should trigger further
inquiry and subsequent treatment.
Physical dependence on AAS may be more insidious than with other drugs.
It is quite likely that the initial involvement with AAS is related to the
anticipated increased physical strength and body mass. Brower proposed a two-
stage model of AAS physical dependence that incorporated the anabolic benefits
early on but that physical dependence ensues after prolonged use of extremely
high doses (159).
Thus, although steroid use disorder with AAS may be rarer than substance
use disorders (SUDs) for other drugs, the prudent clinician will be ever vigilant
to identify the constellation of signs and symptoms that may signify steroid use
disorder. Attempts to label the withdrawal signs and symptoms as opiate-like or
ethanol-like may complicate the issue only because such an effort may conceal a
real dependence on these other drugs. Thus, when obvious signs of distress are
observed during periods of forced abstinence, it is worthwhile to consider the
possibility that the individual may, in fact, have a SUD with other drugs. There
have been a few reports of DSM-defined opioid dependence in bodybuilders
(152,160), and these individuals clearly met the criteria for substance
dependence on both drug classes. Thus, the possibility of polydrug use should
always be considered when dealing with people who use AAS.
Treatment Considerations
AAS users will rarely seek treatment for their unhealthy use. Treating
individuals who have an AAS use disorder has remained challenging for many
of the reasons identified early in this chapter. While there is now evidence for a
role of basic reward mechanisms in the effects of AAS, the impact is modest
when compared to other drugs, and so conventional agonist or antagonist
pharmacotherapies are not useful. Furthermore, a great deal of the “rewarding”
aspects of AAS is their effects on body shape, size, weight, and image—all of
which take time to develop and so the temporal relationship between use and
desired effect is not solidified, making the choice to seek treatment difficult.
Coupled with the attendant desire to perform at a higher level (and the financial
rewards that can follow), treating AAS use disorder is a multifaceted endeavor.
Few empirical studies have been conducted, and current knowledge has
relied on case reports from a handful of clinicians who have treated patients
undergoing acute AAS withdrawal. But, we now have a better understanding of
the constellation of issues that are present; current recommendations for
treatment include a three-pronged approach (161): (a) address the body image
disorder, (b) address the depression due to the hypogonadism during withdrawal,
and (c) address the hedonic effects via pharmacological and psychosocial
treatments. Pharmacotherapy is targeted at restoring the effects of hormonal
imbalance because hypogonadal symptoms can persist for years after cessation
(162,163) and using antidepressants to treat the residual depression that emerges
during withdrawal. As is the case with other forms of SUD, prevention is a
valuable tool to avoid the need for treatment plans. A 2016 report (164) found
that community-based prevention programs that target local gyms may be the
best solution as this strategy will focus on not only where many AAS users
congregate but where most illicit AAS are distributed.
Diagnostic Classifications
While AAS abuse and dependence were acknowledged in the American
Psychiatric Association’s Diagnostic and Statistical Manual of Mental
Disorders, fourth Edition (DSM-IV) (165), it is no longer a specified diagnosis in
DSM-5 (166) and instead is now coded as “other substance use 305.90” and
would be defined as mild, moderate, or severe anabolic steroid use disorder
depending on the number of symptoms that is present. More specific AAS
criteria for classifying a use disorder were proposed to be included in DSM-5
(167), which have been validated in the laboratory (168), but these were not
included. The classification of mild would occur if 2-3 symptoms are present,
while moderate and severe ratings would occur if the patient has 4-5 or more
than 6 symptoms, respectively. The symptoms list is similar to that used in
DSM-IV with items like taking larger amounts of AAS over a longer period of
time; persistent desire or unsuccessful attempts to reduce use; spending a large
amount of time to obtain AAS; experiencing craving or strong desire for AAS;
use having negative impact on work, school, or home; having social or
interpersonal problems with continued use; recurrent use in situations in which it
is physically hazardous to use; continued use despite knowing that its use is
causing problems; tolerance as defined by a need to increase the AAS dose or a
noticeable diminished effect with continued use of the same dose.
There is another factor that must be considered when attempting to diagnose
AAS use disorder. In a study of 108 bodybuilders, Pope et al. (169) noted a
rather high percentage of anorexia nervosa and uncovered a body image disorder
that they labeled reverse anorexia. This condition shares many signs and
symptoms of body dysmorphic syndrome (170). The profile of the former is that
they view themselves as being too small and weak, when they are quite large and
strong. The incidence of this disorder was 8% among AAS users and was not
observed in any of the nonusers. The authors postulate that these body image
disorders may have some influence on an individual’s decision to use AAS.
Because the perceived size, shape, and attractiveness of one’s body are likely
tied to self-esteem (171) and, in general, men want to be 3-lb heavier, be taller,
and have wider shoulders (172), AAS use may be viewed as a way of speeding
up the process to attain physical attractiveness. This similarity in profiles
between body image disorders and drug use might suggest that those who
present with a profile of body image disturbance may respond to the same
treatments that have been used for body dysmorphic syndrome. Serotonin
reuptake blockers have been marginally successful in treating body dysmorphic
disorder (173), and although there have been no published studies to this effect
with people who use AAS, fluoxetine has been marginally successful in a small
sample of bodybuilders who presented with depression during withdrawal from
AAS use (174).
Finally, a recent meta-analysis of 44 studies conducted in 11 countries
revealed some very interesting consistent patterns in the etiology and trajectory
of the initiation of AAS use (175). The majority of the pepeople who use AAS
reported that they began using before the age of 30, participated primarily in
power-related sports, possessed a negative body image, and typically reported
that feelings of depression preceded their use of AAS. These data confirm the
results of other studies showing that psychosocial factors play a significant role
in the decision to begin to use AAS, at least among males.
ABSORPTION AND METABOLISM

Historically, AAS have been taken either orally or injected deep into the muscle
as there are no intravenous formulations or smoked products. More recently,
testosterone gel and patches for topical administration have been released on the
market and offer another route to consider. By far, the greatest influence on
subsequent development of toxic side effects is the route of administration.
About half of an oral dose of testosterone is metabolized via the first-pass effect,
so very large doses are needed. Some 17α-alkylated analogues of testosterone
such as methyltestosterone resist such metabolism and so can be given orally in
smaller doses. The oral route gives rise to many 17-alkylated metabolites, which
are formed in the liver. This overload, not only of the metabolizing enzymes but
also of the parent drug, because the doses taken are so high, causes significant
stress on the liver.
Testosterone is metabolized to 5α-dihydrotestosterone in certain tissues such
as prostate gland, seminal vesicles, and pubic skin. Because 5α-
dihydrotestosterone has two to three times the affinity for the androgen receptor
as the parent hormone, the effects of testosterone are enhanced in these tissues.
One of the more interesting aspects of testosterone’s metabolic pathways is that
it is converted to estradiol in tissues that contain an aromatase enzyme (176).
The biological significance of circulating estrogens in males is unknown, but
they may be involved with sex hormone–binding globulin and lipoproteins.
Further, the estrogen that results from this metabolic process may interact with
estrogen receptors to produce an anabolic effect (136,177). The 17α-alkylated
analogues discussed above are not metabolized to either 5α-dihydrotestosterone
or estrogen. Instead, they interact with the androgen receptor (1,178). Thus, the
overall profile of relative anabolic to androgenic effects is not only due to the
parent compound but to the profile of metabolites that result. With the advent of
widespread use of these drugs during athletic competition, a number of analytic
laboratories have been set up to detect either the parent drug or its metabolites
(179,180). In addition to providing quantitative analyses of the various synthetic
analogues, most labs measure the testosterone/epitestosterone ratio (the T/E
ratio) as a metric of exogenous testosterone administration (181); the threshold
for an acceptable (ie, passing) ratio was originally set at 6:1 but has been
lowered to 4:1, which has caused some controversy. This strategy of testing both
the parent hormone testosterone and its major metabolite has provided a more
reliable method of detecting illicit use of a hormone that is normally found in the
body.
Another important advancement in detecting illicit testosterone use
capitalizes on the natural abundance of 13C and its dissociation from the
abundance of 12C in biological systems (182), and the 13C/12C ratio should
reflect that of the ingested carbon sources. Pharmaceutical grade testosterone is
made from soya bean stigmasterol, which by its nature has a lower 13C content.
Using GC combustion isotope ratio mass spectrometry, these differences can be
detected and used to identify the “source” of the testosterone that is present in a
biological sample.
MECHANISMS OF ACTION
About 95% of the testosterone in males is synthesized in the testes, whereas the
remaining 5% comes from the adrenals. The cholesterol used in the synthetic
pathway comes from acetate that is stored in the testes and not from circulating
blood levels. AAS have long been thought to exert their effects in the periphery,
primarily by increasing the rate of RNA transcription (7,183). About half of the
circulating testosterone is tightly bound to sex hormone–binding globulin, and
the other half is lightly bound to albumin, from which it freely dissociates and
from whence it can diffuse passively into target cells. After attaching to a steroid
receptor in the cytoplasm, the hormone receptor complex moves into the nucleus
where it binds to sites on the chromatin, resulting in the formation of new
mRNA. If the target tissue is skeletal muscle, then new myofilaments are
formed, which causes myofibrils to divide (1,184). Because it is not completely
understood whether this activity occurs at the supraphysiological doses typically
taken by people who use AAS, another mechanism was sought.
The pharmacological profile of the AAS is thought to be due to androgen
binding to intracellular androgen receptors. This process takes about 30 minutes
and ultimately alters gene expression, but it is now believed that AAS possess a
nongenomic action that can be mobilized in seconds or minutes (185). There
have been some advances in the understanding of how testosterone metabolites
interact with the γ-aminobutyric acid (GABAA)/benzodiazepine receptor
complex or dopaminergic neurons in nucleus accumbens to mediate
testosterone’s hedonic effects (186).
It has been suggested that high doses of AAS cross-react with glucocorticoid
receptors that control the catabolic rates of protein (1,187,188). The significance
of the anticatabolic effect of these drugs is often ignored in lieu of the more
direct effect of these steroids on protein synthesis. It is also possible that the
stress of strenuous workouts is not felt by athletes taking AAS because the
stress-induced increase in cortisol is blocked. This action would also permit the
workouts to be longer and more vigorous, further improving performance.
It is possible that the physical changes attributed to a direct effect of AAS on
protein synthesis may be mediated via a direct effect on the central nervous
system. Such effects might result in increased motivation and intensity of
training to a degree that performance is improved. Increased aggressive behavior
may also play a role in the training process. It is likely that the use of
supraphysiological doses of these drugs can have both a direct effect on muscle
tissue and an indirect effect by altering emotions such as motivation and drive
such that the training periods are longer and more productive, resulting in
improved performance.
Additional insight into the effects of AAS on skeletal muscle has been
gleaned using an androgen receptor (AR) knockout mouse model (189). These
authors demonstrated that AR-regulated genes are responsible for the increases
in muscle mass by maintaining myoblasts in a proliferation state and that, in
addition, the AR also suppresses pathways that break down muscle. There have
been some recent advances in the understanding of how testosterone metabolites
interact with the GABAA/benzodiazepine receptor complex or dopaminergic
neurons in nucleus accumbens to mediate testosterone’s hedonic effects (186).
The concept that AAS interact directly with peripheral benzodiazepine receptors
in rat brain was explored over a decade ago (190). These receptors are
mitochondrial proteins that are involved with regulating steroid synthesis and
transport, so it seems plausible that their activation via exogenous AAS could
have an impact on behavior that is mediated by these receptors.
The increase in body weight, especially during the first weeks of use, is
almost certainly attributed to the stimulation of mineralocorticoid receptors,
resulting in sodium and, ultimately, water retention as well as increasing
amounts of circulating estrogen that has been aromatized from testosterone. This
effect gives the muscles, particularly the deltoid, a “puffy” appearance. The
increase in red blood cell production is probably the major reason that long-
distance runners may use these drugs because endurance, rather than bulk
muscle mass, is an asset in this sport. Blood volume probably increases as a
result of erythropoietin synthesis. This effect is due to direct action on the bone
marrow and easily leads to a rise in hematocrit (191).
FUTURE VISTAS
The Healthy People 2020 initiative has specific goals related to AAS use, in
particular, setting goals for reduce steroid use among 8th, 10th, and 12th graders
(192). These drugs continue to be used in unhealthy ways by individuals for a
wide range of reasons. Further, as people who previously used heavy amounts of
AAS enter middle age, it remains to be seen whether there are psychiatric of
other medical consequences of this form of unhealthy drug use (193), an issue
that the clinician may need to address when presented with organ diseases in
individuals who, upon initial presentation, exercised regularly, ate balanced
meals, and did not smoke for the past 30 years. The addiction liability of AAS
may have a central nervous system mechanism that complements the anabolic
effects. As quantitative methods for detecting AAS have become more
sophisticated and specific, individuals have switched to using nutritional
supplements, endogenous peptides such as growth hormone and erythropoietin.
Recent attempts to determine reference ranges for urinary steroid “profiles”
(194) represent a movement that has long been awaited and may help to better
define when illicit use has occurred. Although the anabolic effects of many of
these supplements are not well documented, side effects can still occur and
remain a concern. Selective androgen receptor modulators, capable of increasing
muscle mass with little androgenic effects (and have already been banned from
the Olympics), will join the ranks of the designer AAS like tetrahydrogestrinone
and desoxymethyltestosterone as the performance-enhancing substances of the
future. Indeed, selective androgen receptor modulators have already been
explored and shown to possess tissue-selective anabolic effects on bone mineral
content in female rats, without concomitant side effects (195). While the
designer drugs and novel peptides can now be detected, the way has been paved
for an emerging biotechnique that implements recombinant DNA such that
manipulated genes can be inserted into mammalian cells. This practice, called
gene doping or performance-enhancing genetics, has been defined by the World
Anti-Doping Agency as “the non-therapeutic use of genes, genetic elements
and/or cells that have the capacity to enhance athletic performance” (196). This
commission is unique in that human gene doping has not yet occurred, but the
World Anti-Doping Agency has taken the initiative to set standards for future
events. Conceptually, gene doping would involve using scientific techniques to
manipulate DNA in a manner that would improve athletic performance
(197,198). But, there is a legitimate medical rationale for pursuing the
development of selective androgen modulators because as AAS medications
have been useful in treating a variety of medical conditions (eg, short stature,
burns, wasting syndrome, anemia, and bone disorders), they lack selectivity
(199). The drugs have the potential to target androgen receptors on specific end
organs and, as such, are likely to have a safer profile. Finally, the medical
community needs to appreciate the fact that few people who use AAS will seek
drug addiction treatment, but as they age, the medical consequences of years of
using excessive doses of these agents will take its toll on body organs and may
present the clinician with conditions that will not have an obvious cause.
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CHAPTER 20
Electronic Cigarettes
Gideon St.Helen and Neal L. Benowitz
CHAPTER OUTLINE
E-cigarette, the Product
Constituents of E-Cigarettes and Their Aerosols
Nicotine Delivery and Addiction Potential
Secondhand and Thirdhand Exposure
Prevalence of E-Cigarette Use
E-Cigarette as a Possible Gateway to Combustible Cigarettes
Health Effects of E-Cigarettes
E-Cigarette Use and Stopping SmokingE-cigarettes as a Clinical Tool
What to Tell Patients
Other Electronic Nicotine Delivery Systems
Other Substance Use with E-Cigarettes
Regulation of E-Cigarettes
E-CIGARETTE, THE PRODUCT

Electronic cigarettes (e-cigarettes) are battery-powered devices used to deliver a
nicotine-containing aerosol to the person using it. E-cigarettes contain a battery,
a heating element called an atomizer, and e-liquid, which is usually a solution of
vegetable glycerin (VG) and/or propylene glycol (PG) containing nicotine and/or
flavorants. The invention of the modern e-cigarette is attributed to a Chinese
pharmacist, Hon Lik, in the early 2000s, whose US patent application describes
the e-cigarette as “an electronic atomization cigarette that functions as
substitutes [sic] for quitting smoking and cigarette substitutes” (patent No.
8,490,628 B2) (1). Before Hon Lik, Philip Morris, a tobacco company, and its
affiliates had been developing a nicotine aerosol device similar to the modern e-
cigarette in the 1990s to complement combustible cigarettes (2).
While there is wide variability in current e-cigarette product engineering, for
simplicity, they can be grouped into three main types: cig-a-likes, pen-style tank
e-cigarettes, and advanced personal vaporizers (APVs); 1st generation, 2nd
generation, and 3rd generation are used interchangeably with these three
types, respectively (Fig. 20-1). Cig-a-likes (1st generation) are cigarette-shaped
devices, which consist of a low-capacity battery (~75-150 mAh) and cartridge
containing an atomizer. Cig-a-likes can be disposable or rechargeable, containing
rechargeable batteries and allowing cartridge replacement. Most cig-a-likes are
puff-activated. Popular brands of cig-a-likes include Halo Cigs, Blu E-cigs,
NJOY, and V2 Cigs.
Figure 20-1 Types of e-cigarettes: E-cigarette products. From

right to left, disposable and rechargeable e-cigarettes are also
known as cig-a-likes or 1st-generation e-cigarettes; medium-
size tank devices are also referred to as pen-style or 2nd-
generation e-cigarettes; and large-size tank devices, e-cigar,
and e-pipe are also referred to as advanced personal
vaporizers. Source: 2016 Surgeon General’s Report on E-
cigarette use among youth and young adults.
Pen-style tank e-cigarettes (2nd generation) are larger than a conventional

cigarette or cig-a-like, have higher-capacity batteries (450-1100 mAh), and may
contain a prefilled cartridge or refillable tank. The atomizer is usually a prebuilt
coil made from high-resistance metals/alloys such as nichrome or kanthal,
through which a wick is wound in a tank. Most pen-style e-cigarettes are
activated by a manual switch. Popular brands include KangerTech’s Protank and
EVOD, Aspire ET, and Innokin iClear.
APVs (3rd generation) come in multiple shapes (Fig. 20-1) and are typically
larger than pen-shaped e-cigarettes. These devices consist of high-capacity
batteries (3000-3500 mAh). APVs come in two types: mechanical mods
(modular) and regulated mods. Mechanical mods contain no circuitry and consist
of a battery compartment, a button to activate the device, and a connector to
attach to an e-cigarette tank. Regulated mods are more complex in design,
include electrical circuit boards with built-in features to control voltage and/or
power output (variable voltage/variable wattage) but are more user-friendly than
mechanical mods. Mods are compatible with most standard tanks, including
those used in pen-shaped e-cigarettes. More recent APVs include automatic
temperature control devices that some classify as 4th-generation e-cigarettes.
CONSTITUENTS OF E-CIGARETTES
AND THEIR AEROSOLS
Propylene Glycol and Vegetable Glycerin
The liquid refill, referred to as e-liquid or e-juice, used in e-cigarettes contains
PG and/or VG, nicotine, flavorants, and some contaminants. Propylene glycol
(PG, 1,2-dihydroxypropane) is an odorless, colorless, and tasteless synthetic
liquid. PG, a constituent of theatrical smoke and fog, produces the “smokiness”
of the e-cigarette aerosol. PG also produces the sensory response in the upper
airways colloquially referred to as the “throat hit” (3). Glycerol derived from
vegetable sources (vegetable glycerin, VG), or propane-1,2,3-triol, is an
odorless, colorless, and sweet-tasting viscous liquid. The ratios of VG to PG in
e-liquids vary according to the desired smokiness of the aerosol, sweetness,
viscosity, and throat hit. The concentration of VG and PG in e-cigarette aerosol
depends on their concentration in the e-liquid (4). Importantly, while both PG
and VG are generally recognized as safe for use in food and oral consumption by
the Food and Drug Administration (FDA), there is no such safety assessment or
rating when aerosolized and inhaled directly and at times deeply into the
respiratory system. In addition, heating of PG and VG in high-temperature
conditions can produce toxic by-products such as acrolein, formaldehyde, and
benzene (5,6).
Nicotine
Nicotine levels in e-cigarettes or e-liquids range from low (eg, 3 mg/mL) to high
(eg, 50 mg/mL). Many brands of e-liquids market zero-nicotine options (7),
presumably for nicotine-free vaping or for mixing with other nicotine-containing
e-liquids. In addition, studies have shown poor concordance of labeled and
actual nicotine content of some cig-a-like and refill e-liquid brands (4,8–10),
However, the nicotine level in the e-liquid is not necessarily predictive of
nicotine exposure. The amount of nicotine delivered per puff is highly dependent
on the power applied to the e-cigarette atomizer and the resultant temperature of
the coil (11). For instance, people who use high-powered APVs frequently use
low nicotine concentration e-liquids because of the large amount of aerosol
produced by these devices and resulting high nicotine intake (12).
Flavorants (Flavorings)
Flavorants are an important feature of e-cigarettes. In 2014, over 7700 different
e-liquid flavors were identified in the US marketplace, including tobacco, fruit
and beverage flavors, sweet flavors, menthol, and combinations (7,13). Several
flavorants used in e-cigarettes are toxic and could be harmful to people who use
e-cigarettes. These include diacetyl and 2,3-pentanedione, both of which give a
buttery flavor, and are known causes of bronchiolitis obliterans in humans with
high-level exposure in occupational settings (14,15), and other flavorants such as
cinnamaldehyde, 2-methoxycinnamaldehyde, vanillin, and 2,5-dimethypyrazine
(chocolate flavoring), which have various toxic effects in cells in vitro (16–18).
Health effects of these chemicals have not been demonstrated in humans at the
concentrations commonly found in e-cigarette aerosols. Of note, some flavorants
thermally decompose to toxic and carcinogenic aldehydes in e-cigarettes and at
levels exceeding safety limits (19).
Contaminants
Contaminants in some e-liquids and e-cigarette aerosols include known human
carcinogens such as tobacco-specific nitrosamines (eg, 4-(methylnitrosamino)-1-
(3-pyridyl)-1-butanone, NNK) (20), polycyclic aromatic hydrocarbons, PAHs
(eg, pyrene) (21), heavy metals (eg, cadmium, lead, and copper) (20,22). and
minor tobacco alkaloids (eg, nornicotine and myosmine) (8,10). The
concentrations of these contaminants depend on the quality of the purification
process when nicotine is extracted from tobacco. The metal coils of the atomizer
and soldering in e-cigarettes are sources of heavy metals such as chromium
(likely in the trivalent state, chromium III), nickel, and tin (22). While
hexavalent chromium (chromium VI) is a known human carcinogen, there is no
evidence that it is emitted from e-cigarettes (23). When present, contaminants in
e-liquids and aerosols are present at much lower levels (9-450 times lower)
compared to conventional cigarettes and cigarette smoke (20). This would
suggest that the carcinogenic risk is lower for e-cigarettes compared to
conventional cigarettes. Implications of lower contaminant levels in e-cigarette
aerosol for respiratory and cardiovascular disease risks are still uncertain given
the presence of reactive aldehydes and toxic volatile organic compounds in e-
cigarette aerosols.
Volatile Organic Compounds

Volatile organic compounds (VOCs) are a class of compounds produced from
incomplete combustion of organic materials. Because of their abundance in
tobacco smoke and their inherent carcinogenicity and/or toxicity, risk assessment
models indicate that VOCs account for the majority of cancer, cardiovascular,
and respiratory disease risks of tobacco smoke (24,25). Although e-cigarettes do
not burn (pyrolyse) the e-liquid, the heat applied by the atomizer can lead to
temperature-dependent thermal decomposition of e-liquid constituents to toxic
VOCs (26). Under certain conditions (high power and dry puffs), VOCs such as
formaldehyde, acetaldehyde, and acrolein are emitted in e-cigarette aerosol at
pharmacologically significant levels, within the range of that achieved from
smoking conventional cigarettes (20,26–29).
One study reported that formaldehyde is generated from e-cigarettes at levels
that are five times higher compared to conventional cigarettes (27). VG and PG
both degrade to toxic aldehydes when heated (5,6), and a recent study suggests
that flavoring compounds can also be substantial sources of aldehydes (19).
Whether people who use e-cigarettes actually use their devices under conditions
that generate high levels of aldehydes has been questioned because the resultant
aerosol would be harsh and unpleasant tasting (28).
Acrolein, a cardiopulmonary toxicant, is estimated to account for as much as
88.5% of the noncancer risk index of tobacco smoking (25). Studies of people
who use e-cigarettes assessing urine biomarkers of acrolein exposure found
much lower levels than those of tobacco smokers and similar to levels in
nonsmokers, suggesting that actual levels of exposure and health risks from
acrolein are low (30–33). However, high-powered e-cigarettes may deliver high
levels of acrolein and other aldehydes, comparable to conventional cigarettes;
acrolein biomarker studies with such products have not yet been published.
Importantly, one of the major health risks from smoking cigarettes is from
cardiovascular disease (34). Because cardiovascular disease risk is nonlinear
with cigarette consumption, smoking just a few cigarettes per day imparts a
majority of the cardiovascular disease risk. Thus, if VOCs such as acrolein are
delivered in significant amounts from e-cigarettes, these compounds could
contribute to cardiovascular disease risk.
Particles
Epidemiological studies have long associated exposure to particles, particularly
fine particles (those <2.5 μm in aerodynamic diameter) and ultrafine particles
(those <0.1 μm), in ambient air to increased risk of various cancers,
cardiovascular, and respiratory diseases (35–37). Both tobacco smoke and e-
cigarette emissions are best described as aerosols, that is, solid or liquid particles
suspended in air. Particle size is an important factor in predicting the deposition
fraction of the inhaled particles in various regions of the respiratory tract (38),
which in turn predicts the extent of nicotine absorption in the case of smoked or
vaped tobacco products. Mainstream tobacco smoke (the smoke inhaled) has a
median particle size range of 180-340 nm (39).
Initial studies reported that e-cigarettes have similar particle size compared
to mainstream tobacco cigarette smoke (40), including some particles in the
nanoparticle range (41,42). A recent study corroborated the initial studies,
reporting that e-cigarette aerosol is bimodal, with median diameter at the modes
of 11-25 nm and 96-175 nm.43 This study found comparable particle
concentrations in each mode and only nanoparticles present during “dry puffs.”
Dry puffs occur when sufficient e-liquid is not drawn into the atomizer chamber
during puffing and the wicking material (eg, cotton) overheats and burns. The
aerosol or smoke given off is described to produce an unpleasant sensory
response in the throat.
The composition of e-cigarette particles is quite different from that of
particles in cigarette smoke (combusted tobacco). Cigarette smoke particles are
much more complex, include solid carbonaceous materials, and persist in the
environment much longer than e-cigarette particles. The larger e-cigarette
particles are liquid, comprised mostly of PG and VG, and such particles would
be expected to dissolve and be absorbed quickly in the lung. Although
constituents of e-cigarette nanoparticles have not been fully characterized,
metals such as tin, chromium, and nickel have been detected in nanoparticles.22
There is also concern about the health consequences of exposure to e-cigarette–
related nanoparticles because these particles can penetrate more deeply into the
lungs (where particle clearance is slower (44)) than particles from combusted
tobacco, leading to longer exposure times to toxicants (including carcinogens)
associated with the particles. The hazards posed by particles generated by e-
cigarettes are at this time unknown, but remain of significant concern warranting
more research.
NICOTINE DELIVERY AND ADDICTION

POTENTIAL
Early studies estimating nicotine delivery from e-cigarettes were based on
modified International Organization for Standardization (ISO) smoking machine
tests or from the volume of e-liquid consumed. These studies showed that e-
cigarettes delivered less nicotine than tobacco cigarettes (9,45,46). The average
nicotine yield for conventional cigarettes is between 0.5-1.5 mg per cigarette
(47). Early pharmacokinetic studies of cig-a-like–type e-cigarettes reported very
low plasma nicotine levels, indicative of low nicotine delivery and/or absorption
(48,49).
A second wave of pharmacokinetic studies has reported higher plasma
nicotine concentrations among people experienced with e-cigarettes (50–52),
although the average maximum plasma nicotine concentrations were lower than
previously reported levels from smoking conventional cigarettes (~15-30 ng/mL)
(47). Second-generation (tank-style) e-cigarettes produce greater increases in
plasma nicotine than first generation (cig-a-likes) (52,53). The latest
pharmacokinetic studies show e-cigarettes delivering similar levels of nicotine to
people who use e-cigarettes compared to conventional cigarettes. One study of e-
cigarette use among people experienced with using them reported that e-
cigarettes delivered an average of 1.3 mg (range 0.4-2.6 mg) of nicotine from 15
puffs, similar to conventional cigarettes, and several people who used e-
cigarettes achieved conventional cigarette–like plasma nicotine levels (4).
Another study among people experienced with e-cigarette use reported that those
who used high-powered APVs were able to mimic the nicotine pharmacokinetic
profile of conventional cigarettes (12).
Pharmacokinetic parameters such as maximum plasma nicotine
concentration (Cmax) and time to maximum concentration (Tmax) are important
determinants of tobacco product addiction liability. Nicotine peaks in blood
within 2-5 minutes after the last puff of an e-cigarette (4,50), relatively similar to
conventional cigarettes (47). Based on the type of e-cigarette, the maximum
blood nicotine levels can be comparable to that from conventional cigarettes.
The basic shape of the plasma nicotine concentration-time curve after single
administration (eg, 10-15 puffs) of nicotine from e-cigarettes is also comparable
to conventional cigarettes, that is, rapid increase in blood nicotine levels
followed by quick decline. This indicates that e-cigarettes have the potential to
initiate and sustain nicotine addiction. Further supporting risk for creating
nicotine addiction, e-cigarettes reduce the urge to smoke and alleviate nicotine
withdrawal symptoms (negative reinforcement) and are rated as satisfying by
people who use them (positive reinforcement) (49,51,54,55). In addition to
nicotine pharmacological effects, oral and tactile sensations may also contribute
to the subjective effects of e-cigarettes and their addictiveness (49).
Nicotine intake and vaping behavior during ad libitum access to e-cigarettes
should be considered when assessing the addictiveness of e-cigarettes. Blood
nicotine levels during ad libitum access rise gradually to a maximum level, in
contrast to the rapid increase in blood nicotine levels that is characteristic of
tobacco smoking and controlled e-cigarette use (12,50,56). People who use e-
cigarettes sustain their blood nicotine levels by vaping intermittently, often in
single or groups of 2-5 puffs (56). Given that a rapid rise in plasma nicotine is
associated with greater addiction liability of tobacco products, and given that e-
cigarettes can deliver nicotine in a near-bolus dose, the addictiveness of e-
cigarettes likely depends on the manner in which they are used.
The relative level of DSM-IV–defined nicotine dependence among adults
who use e-cigarettes compared to conventional cigarettes was examined in the
Population Assessment of Tobacco and Health (PATH) study (57). The PATH
study is a nationally representative longitudinal study of tobacco use in the
United States. Using baseline data collected in 2013 and 2014, addiction-related
criteria were compared in people who exclusively used e-cigarettes and those
who exclusively smoked conventional cigarettes. Based on a number of criteria
including time to first use after waking, considering oneself addicted, strong
cravings, difficulty in refraining from use, and feeling like they really needed the
product, the people who used e-cigarettes self-reported lower scores than
conventional cigarette smokers. While lower scores were self-reported than
conventional cigarette smokers, 77% of people who used e-cigarettes (vs. 94%
of smokers) still considered themselves addicted to e-cigarettes. The reason for
higher self-reported addiction to conventional cigarettes may relate to
differences in nicotine delivery and pharmacokinetics, but may also be related in
part to perceptions of lower risk of addiction to e-cigarettes compared to
conventional cigarettes, a younger age of the user, a shorter lifetime use of e-
cigarettes—as e-cigarettes have been in the market for only a fraction of the time
compared to conventional cigarettes—or more stigma from smoking
conventional cigarettes versus vaping. Greater addictiveness of conventional
cigarettes may also be related to other constituents of tobacco smoke that
enhance the addictiveness of nicotine. For example, cigarette smoke generates
chemicals that inhibit brain monoamine oxidase, which results in higher and
more sustained levels of dopamine following nicotine self-administration.
Rodents treated with monoamine oxidase self-administer nicotine more readily
that control animals.58
Further, some adolescents modify the e-cigarette to increase the “hit” due to
increased nicotine delivery. An example of this is “dripping,” where the nicotine
refill liquid is dripped directly onto the coil. One-quarter of adolescents who use
e-cigarettes have engaged in “dripping” in a recent survey, and manufacturers
are reportedly making their coils more accessible to enable this practice.59
SECONDHAND AND THIRDHAND

EXPOSURE
Unlike conventional cigarettes, e-cigarettes do not generate sidestream
emissions, but bystanders can be exposed to constituents in the aerosol exhaled
by the user. Twenty-four percent of middle and high school students reported
secondhand e-cigarette aerosol exposure in the 2015 National Youth Tobacco
Survey (60). One study measured nicotine in indoor air of the homes of
nonsmoking volunteers who lived with conventional cigarette smokers, with
people who use e-cigarettes, or in control homes where tobacco or e-cigarettes
were not used and measured cotinine in saliva and urine of the nonsmoking
volunteers as a biomarker of exposure to secondhand smoke or to nicotine-
containing e-cigarette aerosol. Air nicotine concentration was higher in the e-
cigarette homes compared to the smoke-free homes, but lower than in the
conventional cigarette homes. Saliva and urine cotinine were 2 and 1.4 times
higher, respectively, in nonsmokers in the conventional cigarette homes
compared to the e-cigarette homes (61). The results of this study suggest that
people who do not use e-cigarettes who live in homes where e-cigarettes are
used are exposed to nicotine derived from the exhaled aerosol, but at lower
levels than people exposed to secondhand cigarette smoke.
In another study, a group of never-smokers participated in three conditions: a
control session without smoking/vaping or passive exposure, passive
conventional tobacco smoke exposure session, and passive e-cigarette aerosol
exposure session (62). After an hour of exposure to conventional tobacco smoke
or to e-cigarette aerosol, serum cotinine concentrations were not significantly
different. Changes in lung function (the ratio of forced expiratory volume in 1
second [FEV1] to forced vital capacity [FVC], FEV1/FVC) were smaller after
passive exposure to e-cigarette aerosol compared to after passive exposure to
conventional cigarette smoke. Another study reported elevated levels of fine
particulate matter (PM2.5), 1,2-propanediol, glycerin, and nicotine in indoor air
and increased levels of nitric oxide (FeNO) release in nonuser volunteers after 2
hours of secondhand e-cigarette exposure (63). Other studies have also measured
increased levels of PM2.5 in indoor air following e-cigarette use (64).
Of further concern is the contribution of e-cigarette emissions to thirdhand
smoke exposure and its potential health effects. Thirdhand tobacco smoke is the
result of physical and chemical transformations of smoke constituents in indoor
and outdoor environments over time, which result in the creation of secondary
pollutants (65). Nicotine reacts with nitrous acid, a ubiquitous environmental
contaminant, to form the potent lung carcinogen 4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) (66). Nicotine has been measured in the indoor
environment after e-cigarette use and is therefore a potential source of thirdhand
smoke exposure (63,67). Despite a lack of human health studies on the long-term
health effects of thirdhand smoke exposure, animal and in vitro studies show that
it has toxic effects on several organs, including the liver and lungs, and is
genotoxic (68,69).
PREVALENCE OF E-CIGARETTE USE

The latest US national data on e-cigarette use among adults are derived from
baseline data of the PATH study, which were collected in 2013 and 2014 (70).
Overall, 6.7% of adults had used e-cigarettes at least once in the previous 30
days compared to 22.5% who had smoked conventional cigarettes, 7.2% who
had smoked any cigar, and 2.2% who had used hookahs at least once in the past
30 days. Current regular use of e-cigarettes among adults, defined as use of e-
cigarettes every day or some days in the past 30 days, was 5.5%. In comparison,
current regular use of conventional cigarettes, any cigar, or hookah was 18.1%,
7.8%, and 4.2%, respectively. Current regular use of conventional cigarettes
indicates that the individual had smoked at least 100 cigarettes in his or her
lifetime and now smoked conventional cigarettes every day or some days.
Current regular use of any cigars was defined similar to e-cigarettes. For
hookahs, current regular use indicates that the participant now uses the product
every day, some days, usually weekly, or usually monthly.
Among adults who use tobacco, 62.2% used one product, 22.5% used two
products, and 15.3% used three or more tobacco products (70). Multiple product
use combined for 37.8%. Among people who use multiple-products, the most
common combination was conventional cigarettes plus e-cigarettes (23%),
followed by conventional cigarettes and hookahs (6%) and conventional
cigarettes and cigarillos (5%).
Additional national data on e-cigarette use among adults were obtained from
the 2014 National Health Interview Survey (NHIS), which estimated that 12.6%
of adults had ever tried e-cigarettes and 3.7% were currently using (at least once
in previous 30 days) (71). (This is the first year e-cigarette use was included in
that survey.) Prevalence of e-cigarette use differed by sex, age, and race. Men
were more likely to have tried e-cigarettes than women; prevalence of ever use
among adults aged 18-24 years was 20% and prevalence decreased with age.
Non-Hispanic American Indian or Alaska Native adults (20.2%) and non-
Hispanic White adults (14.8%) were more likely to have tried e-cigarettes than
Hispanic (8.6%), non-Hispanic Black (7.1%) and non-Hispanic Asian (6.2%).
Current use was not different by sex and was higher among non-Hispanic
American Indian or Alaska Native adults (10.7%) and non-Hispanic White
adults (4.6%) than among Hispanic (2.1%), non-Hispanic Black (1.8%), and
non-Hispanic Asian (1.5%) adults.
Among adults who had ever tried e-cigarettes, 47.6% were current
conventional cigarette smokers, 55.4% were recent former cigarette smokers
who had quit cigarettes less than a year ago, 8.9% were long-term former
smokers (quit for over a year), and 3.2% were never cigarette smokers. In
comparison, among adults who currently use e-cigarettes, 15.9% were current
cigarette smokers, 22.0% were recent former cigarette smokers, 2.3% were long-
term former cigarette smokers, and 0.4% were never-smokers (71). Most adults
who use e-cigarettes are either dual users or occasional users; there are relatively
few people who exclusively daily use e-cigarettes (57). Thus, because most
people who use e-cigarettes still use combusted cigarettes, the risk for many
smoking-related illnesses may not be reduced by incomplete replacement of
smoked cigarettes with e-cigarettes.
The 2015 National Youth Tobacco Survey (NYTS) found that an estimated
27.1% of US youth had ever tried e-cigarettes, which included 13.5% of middle
school students and 37.7% high school students (72). This represents an increase
over previous years (73). Among middle school and high school students, ever
use of e-cigarettes was not different by sex, but was higher among Hispanic
middle school students compared to students of other racial/ethnic backgrounds.
Hispanic and White high school students had ever tried e-cigarettes at higher
rates compared to Black youth (72). Prevalence of current (past 30-day) use
among middle and high school students was 5.3% and 15.5%, respectively,
increasing from 3.9% and 13.4% in 2014, respectively. Of those people who
were currently using in 2015, 0.6% of middle school students and 2.5% of high
school students used e-cigarettes on at least 20 days of the past 30 days.
The US national Monitoring the Future (MTF) survey found that prevalence
of past 30-day use among 8th, 10th, and 12th graders in 2015 was 9.5%, 14%,
and 16%, respectively (74). On average, students used e-cigarettes on <6 days in
the previous 30, regardless of smoking status (75).
In Wave 1 of PATH (2013/2014), ever use of conventional cigarettes, e-
cigarettes, any cigar, and hookah was 13.4%, 10.7%, 7.5%, and 7.5%,
respectively, among youth (12- to 17-year-olds) (70). In that same period,
current use of conventional cigarettes, e-cigarettes, any cigar, and hookah was
4.6%, 3.1%, 2.5%, and 1.7%, respectively. The prevalence of multiple-product
use was 43.0%; 15% used conventional cigarettes and e-cigarettes, 10% used
conventional cigarettes and cigarillos, and 5% used conventional cigarettes and
hookahs.
E-CIGARETTE AS A POSSIBLE
GATEWAY TO COMBUSTIBLE
CIGARETTES
Use of e-cigarettes among youth is strongly associated with use of other tobacco
products. For example, the 2015 NYTS found that 58.8% of high school
conventional cigarette smokers and smokers of other combustible tobacco
products only, as well as 77% of conventional cigarette, other combustible, and
noncombustible product users, also used e-cigarettes in the past 30 days (72).
There is concern among researchers and policymakers that nonsmoking people,
particularly youth, who use e-cigarettes might become users of combustible
tobacco products. In other words, e-cigarettes might be serving as a “gateway” to
combustible cigarette use and lifelong addiction on tobacco. One mechanism by
which a gateway effect might occur is by adversely affecting the maturation of
the adolescent brain, an action of nicotine that has been demonstrated in rodents
(76,77). Nicotine results in delayed maturation of the prefrontal cortex, which
can in turn result in impaired executive function and greater impulsiveness.
Whether this occurs with exposure to nicotine at levels that occur in most
adolescents is unclear.
Several prospective, longitudinal studies of nonsmokers found that youth
and young adults who had used e-cigarettes were 2-8 times more likely to
initiate use of conventional cigarettes than those who had never used e-cigarettes
(78–82). Adolescents who use flavored e-cigarettes are more likely to want to try
conventional cigarettes (83).
One study found that the association between e-cigarette use and
conventional cigarette initiation was stronger (odds ratio = 9.69, 95% CI, 4.02-
23.4) for youth who were not originally susceptible to cigarette smoking
(defined as those with a firm commitment not to smoke) compared to those who
were susceptible (81). This suggests that e-cigarette use might expand the pool
of adolescents who will eventually smoke conventional cigarettes, thus
unfavorably impacting the incidence of conventional cigarette use among adults.
However, none of these studies provides confirmation on whether youth who
first used e-cigarettes and then tried cigarettes became regular smokers or will
become addicted adult smokers. Most studies did not control for use of other
drugs like marijuana. Other limitations include the use of “any e-cigarette use”
as a measure of e-cigarette use, resulting in inability to describe the dose–
response relationship between extent of e-cigarette use and subsequent
combustible tobacco use, and small sample sizes (72). Thus, it is unknown
whether experimentation with e-cigarettes represents a significant risk for later
addictive cigarette smoking. Internationally, in Poland, increases have been seen
in adolescent e-cigarette use among those who never previously smoked
conventional cigarettes, and dual use is increasing in some countries (84). In the
United States, current conventional cigarette use among high school students
dropped from 22.6%-13.6% in 2007 when e-cigarette entered the US market and
continued declining to 7.0% in 2015 (74). It is reassuring that while e-cigarette
use in the United States has increased markedly in recent years, the prevalence
of conventional cigarette smoking has steadily declined, arguing against any
large gateway effect (74).
HEALTH EFFECTS OF E-CIGARETTES

The potential adverse health effects of e-cigarettes among people who do not use
e-cigarettes is of concern. However, among conventional cigarette smokers, the
relative risk of e-cigarette compared to conventional cigarette use is an important
consideration in determining the population-level benefit versus risk of e-
cigarette use. Few studies are available on the effects of e-cigarette use on
incidence of disease in people. Such studies are difficult to conduct because most
people who use e-cigarettes are current or former smokers (and already suffer
adverse health effects from smoking). Furthermore, there are relatively few
people who use only e-cigarettes, and most of those have not used e-cigarettes
for very long. The most common side effects of e-cigarettes are throat irritation
and cough (85).
As described previously, e-cigarettes may expose people who use them to
some of the same potentially toxic constituents of cigarette smoke, including
nicotine, oxidant chemicals, aldehydes, particles, and metals, although often in
much lower levels than those found in cigarette smoke. Moreover, e-cigarette
use may expose people who use them to toxic substances not present in smoked
cigarettes, such as those from humectant (PG, VG), e-cigarette hardware (tin
particles from faulty solder joints), and to some flavor chemicals that are not
present in conventional cigarette smoke. On the other hand, e-cigarettes do not
expose people who use them to carbon monoxide, which is a known
cardiovascular and reproductive toxin. The major health effects of cigarette
smoking are cardiovascular disease, chronic obstructive lung disease, cancer,
infectious disease, and reproductive toxicity. The potential adverse effects of e-
cigarettes with respect to these diseases are discussed below.
Cardiovascular toxicity of smoking is thought to involve a number of
pathophysiological effects including oxidant stress, hemodynamic stress,
inflammation, endothelial dysfunction, thrombosis, and arrhythmogenesis. The
main chemical mediators of these actions are the combustion products in smoke,
but nicotine might contribute to some extent as well (86,87). The major
cardiovascular effect of e-cigarettes in people reflects the sympathetic nervous
system stimulating effect of nicotine. Thus, e-cigarette use increases heart rate
and blood pressure, increases arterial stiffness, and reduces heart rate variability,
all actions related to sympathetic stimulation (88,89). Acute e-cigarette use
causes endothelial dysfunction, which could be mediated by nicotine and/or by
oxidants or particulates in e-cigarette emissions (90). Thrombosis is a central
mechanism of acute cardiovascular events caused by smoking, but nicotine does
not activate platelets in people. In vitro platelet activation with exposure to e-
cigarette aerosol has been reported and oxidation of blood lipids in people who
use e-cigarettes has been observed (88,91). Although inflammatory effects of e-
cigarette aerosol exposure are seen in human airway epithelial cells and human
neutrophil in vitro (92), increases in inflammatory markers in people who use e-
cigarettes have not been reported (88,93–95). While e-cigarette use acutely
increases blood pressure, studies of smokers with hypertension showed reduction
in blood pressure when they switched to e-cigarettes compared to baseline
(96,97).
Since e-cigarette use exposes people to nicotine at levels comparable to that
of cigarettes, data on the cardiovascular safety of nicotine in people who use
tobacco may be relevant. Research on people who use smokeless tobacco (snus)
in Sweden is particularly informative because a large proportion of Swedish men
use snus but do not smoke cigarettes, exposing them to nicotine for many years
without the combustion products from cigarettes. As reviewed recently (86),
unlike cigarette smoking, snus use does not activate platelets or accelerate
atherogenesis (based on carotid intima thickness, a noninvasive measure of
atherosclerosis). The incidence of acute myocardial infarction (MI) and stroke is
not higher in people who use snus compared to people who do not use tobacco
products, but there is a small but significant increase in fatal MI or stroke. One
retrospective study found that in people who use snus who had an acute MI,
mortality in the subsequent 2 years was higher in those who continued to use
snus compared to those who quit. Thus, there is concern that nicotine per se may
pose some cardiovascular hazard, particularly in people with underlying
cardiovascular disease. The same is likely to apply to people who use e-
cigarettes.
Cell and animal studies find that e-cigarette liquids and aerosol can cause
cytotoxicity, oxidant stress, inflammation, and impaired host defenses, the latter
resulting in reduced capacity to fight viral or bacterial lung infections (94,98–
100). Exposure to e-cigarette vapor, as short as 1 hour, induced
proteostasis/autophagy impairment and aggresome formation in Beas2b cells,
indicating that e-cigarette exposure may increase the risk of emphysema/chronic
obstructive pulmonary disease (COPD) (101). These studies have raised
concerns about pulmonary toxicity of e-cigarette aerosol. Laboratory-based
human studies have reported reduced pulmonary compliance and reduced
expired nitric oxide, consistent with pulmonary irritation and oxidant stress
(102). A study in adolescents reported an association between e-cigarette use and
bronchitis symptoms (103). However, smokers with asthma or COPD
demonstrated improved symptoms and improved pulmonary function tests when
they used e-cigarettes and either quit or reduced cigarette consumption,
suggesting pulmonary disease harm reduction (104–106). It is possible that e-
cigarettes could both cause respiratory symptoms in healthy adolescents who do
not smoke cigarettes or in those exposed to secondhand e-cigarette aerosol,
while being less toxic than cigarettes, also reducing symptoms when substituted
for cigarettes by smokers with pre-existing lung disease. However, this is as yet
unknown.
No data are available on e-cigarette use and cancer risk in humans. Nicotine,
a constituent in e-cigarette liquid and aerosols, has the potential to promote
cancer; this has been demonstrated in some animal studies (107,108) but not in
others (109,110). However, epidemiological data from people who use snus in
Sweden do not demonstrate an increased incidence of cancer (other than
nitrosamine-related esophageal and pancreatic cancer), which argues against a
cancer promotion effect. Long-term use of NRT has also not been found to be
associated with increased risk of cancer (111). Other chemicals in e-cigarette
liquid and/or aerosol may be genotoxic and potentially cause DNA damage,
which can initiate carcinogenesis (112,113). Studies are needed to understand the
carcinogenic potential of e-cigarettes, particularly that of additives and
chemicals given off in e-cigarette aerosol, as well as robust longitudinal studies
on association between e-cigarette use and cancer risk. Reproductive toxicity is
thought to be related at least in part to nicotine exposure during fetal
development and the use of e-cigarettes may pose similar risk (114). This hazard
has not yet been empirically studied.
Nicotine itself in high doses can be toxic or even fatal. Nicotine toxicity,
including some fatalities, has been reported in children who ingested e-cigarette
liquids (115). From September 2010 to February 2014, US poison centers
reported 2405 e-cigarette exposure calls about possible e-cigarette liquid toxicity
(116); most victims experience minimal toxicity (117). Child-resistant e-liquid
bottles are increasing more common and should be mandated for all e-liquid
solutions. A number of cases of exploding e-cigarette batteries have been
reported, some associated with serious burns (118).
While e-cigarettes may pose some risk for cardiovascular and pulmonary
disease, particularly for people with underlying cardiopulmonary disease, based
on quantitative and qualitative comparisons and limited clinical data, the risk of
e-cigarettes is most likely less than that of conventional cigarette smoking, but
most likely greater than not smoking any tobacco product. A caveat is that e-
cigarette devices differ markedly in emissions and volume of aerosol generated,
which could result in different cardiopulmonary risk for different products
E-CIGARETTE USE AND STOPPING

SMOKINGE-CIGARETTES AS A
CLINICAL TOOL
Smokers report that they use e-cigarettes for several reasons, including for
curiosity, because e-cigarettes are perceived as less harmful than cigarettes, to
help quit smoking, to reduce smoking, to vape in places where smoking is
forbidden, and for lifestyle reasons. An assessment of the risks versus benefit of
e-cigarettes in the general population is strongly influenced by the net effect of
e-cigarette use on the prevalence of cigarette smoking. Using e-cigarettes to aid
stopping smoking has been studied in a few clinical trials and in population
studies where e-cigarettes were purchased by consumers for self-managed
cessation.
Three randomized clinical trials of e-cigarettes to aid tobacco treatment have
been published. Two of the studies, using e-cigarette devices that delivered low
levels of nicotine, found that e-cigarettes increased quit rates compared to
placebo e-cigarette and comparable to nicotine patch, but rates were low
(119,120). The first and often-cited study (Bullen et al.) was a quitline-based
study in New Zealand that randomized smokers to e-cigarettes with or without
nicotine (16-mg nicotine cig-a-like) and nicotine patch (21-mg nicotine).
Nicotine e-cigarette use resulted in increased biochemically verified abstinence
at 6 months compared to placebo e-cigarette use [relative risk (RR): 1.77, 95%
CI, 0.54-5.77] and compared to nicotine patch [RR: 1.26 (0.68-2.34)]. There was
no difference between active e-cigarette and placebo at 3- and 6-month outcomes
for both continuous and 7-day point prevalence of smoking abstinence.
Limitations include that the e-cigarettes were mailed directly to participants
while NRT was obtained through a voucher system that the participants had to
take to a community pharmacy. As well, e-cigarette dosing was unlimited in both
quantity and frequency in this population of smokers with a “high” level of
physical dependence, while the nicotine patch dose was limited to only 21 mg
(“high” levels of physical dependence often require nicotine patch doses well
above 21 mg, suggesting that this study capped the patch dose at too low a
level).
In the second study (Caponnetto et al.), participants were randomized to
three groups: (A) 7.2-mg nicotine e-cigarette (cig-a-like) and followed for 12
weeks, (B) 7.2-mg nicotine for 6 weeks followed by 5.2-mg nicotine for 6
weeks, and (C) placebo e-cigarette. Complete abstinence at 12 weeks in groups
A, B, and C were 11.0%, 17.0%, and 4%, respectively. Pooled relative risk of
abstinence in the nicotine versus placebo groups was 2.75 (0.97-7.76). The study
also showed that use of e-cigarettes, with or without nicotine, decreased cigarette
consumption. The study did not have a control group, and the subjects had no
intention to quit, making comparisons with double-blinded placebo-controlled
studies of smokers desiring to quit (a standard for FDA-approved tobacco
pharmacotherapies) unrealistic.
A third trial (Adriaens et al.) using more advanced e-cigarette devices
showed benefit both for abstinence and smoking reduction (121). Participants
were randomized to either a Joyetech or Kanger T2, both used with 18 mg/mL e-
liquid, and a control group. At 8 weeks, 34% of the two e-cigarette groups had
stopped smoking tobacco cigarettes, versus 0% of the control group. Due to the
small numbers of subjects and low quit rates, these trials have been assessed in a
Cochrane review to be of low quality (122). A controlled trial of e-cigarette use
for smoking reduction found that use of a first-generation e-cigarette was
associated with a greater likelihood of 50% cigarette reduction at 3 weeks [OR =
3.20, 1.09-9.37] (123). Several uncontrolled studies also found e-cigarette use
associated with quitting smoking (124–126). One of these studies found that quit
rates were higher when e-cigarettes were used in combination with varenicline
compared to e-cigarette alone use (127).
The most recent systematic review and meta-analysis were conducted to
investigate the impact of e-cigarettes on long-term tobacco use (128). The
analysis included the three randomized controlled trials and nine prospective
cohort studies. For the clinical trials, pooled risk ratios for stopping smoking for
e-cigarette versus placebo e-cigarette was 2.03 (0.94-4.38) and for e-cigarette
versus nicotine patch, 1.10 (0.60-2.03). For the cohort studies, odds ratio of
stopping smoking with e-cigarettes was 0.74 (0.55-1.0001). Although
inconclusive, these results are consistent with findings of other systematic
reviews/meta-analyses (129,130).
E-Cigarette Use and Stopping Smoking at the

Population Level
There is evidence that use of e-cigarettes is associated with increased stopping
smoking at the population level. An analysis of repeated cross-sectional data
from five waves of a large, nationally representative survey in the United States
(U.S. Current Population Survey-Tobacco Use Supplement [CPS-TUS]) found
significantly higher population stopping smoking rate in 2014–2015 compared to
2010–2011 (5.6% vs. 4.5%, an increase of 1.1%) (131). The study also found
that people who use e-cigarettes were more likely than people who did not to
attempt to quit (65.1% vs. 40.1%) and were more likely to succeed in quitting
(8.2% vs. 4.8%). Population-based studies in the United Kingdom in people who
self-selected e-cigarette use found substantially higher quit rates with use of e-
cigarettes compared to use of other over-the-counter nicotine replacement
therapy (132–134). E-cigarettes were most effective when more advanced
devices were used and when e-cigarettes were used daily (135). A longitudinal
cohort study in the United Kingdom found that e-cigarette use at 1 year was
associated with increased smoking quit attempts but not cessation (136). Another
cohort study in the United States found no overall effect of e-cigarette use on
stopping smoking, but people who regularly used e-cigarettes were six times
more likely to quit smoking (abstinent for a month) than people who used
nondaily (137). Other studies in which smokers reported e-cigarette use at
baseline and smoking status at a later time found that cessation rates were lower
in people who had used e-cigarettes in the past (130). A potential bias in these
studies is that people who used e-cigarettes who had quit smoking using e-
cigarettes at baseline would have been excluded from the analysis. Other
limitations include no information available on the reason for e-cigarette use (eg,
intent to quit) or on the type and frequency of e-cigarette use, all of which may
influence stopping smoking. Another factor that may influence the impact of e-
cigarette use on smoking is the policy environment in the particular country.
Self-reported stopping smoking with e-cigarette use is higher in countries with
less restrictive e-cigarette policies compared to countries with more restrictive
policies (138).
The available evidence regarding e-cigarette use to aid tobacco treatment is
promising for smokers who are intending to use e-cigarettes to quit and willing
to use e-cigarettes regularly, but requires more study. Further studies are needed
to establish the role and optimal methods of use of e-cigarettes in the tobacco
treatment arm. Given that e-cigarette use is not harmless, any use of them to help
stop smoking combusted cigarettes should be viewed as a harm reduction
strategy—unless the user is able to eventually also quit the e-cigarette. At
present, controlled clinical trials of e-cigarettes for tobacco treatment cannot be
conducted in the United States because an investigational new drug approval
from the FDA is required, which has not been possible due to lack of the
required toxicology testing. Clinical trials are ongoing elsewhere in the world.
WHAT TO TELL PATIENTS

The most important action a person who smokes cigarettes can take to improve
health is to stop smoking. Clinicians should support a person’s attempt to quit
and try to ensure that advice given does not undermine the motivation to quit.
The safest and proven pharmacological aids for tobacco treatment are nicotine
replacement products, varenicline, and bupropion, as well as off-label
medications (nortriptyline, etc.).
There are conflicting opinions about what clinicians should do when people
who smoke ask about the use of e-cigarettes to help them quit smoking (139).
Acknowledging the controversy, we offer the following recommendations,
which are supported by the American Heart Association (140). If a person has
failed initial treatment, has been intolerant of or refuses to use approved
medications and psychotherapies, and wishes to use e-cigarettes to aid quitting,
we believe that attempt should be supported. People who smoke should be
informed that, although e-cigarettes are likely to be less harmful than cigarette
smoking, the products are unregulated and deliver toxic chemicals and their
long-term health effects are unknown. Furthermore, while many people who
smoke have stated that they have been helped by e-cigarettes, the benefit of e-
cigarettes for quitting smoking has not been proven by controlled clinical trials,
the standard used for regulatory approval. People who use e-cigarettes to help
quit smoking should be encouraged to quit smoking completely as soon as
possible, as smoking, even at reduced levels, is still harmful to health. Finally,
we recommend that people who have quit smoking using e-cigarettes be urged to
set a quit date for the e-cigarette use itself and not plan to use e-cigarette
indefinitely.
OTHER ELECTRONIC NICOTINE

DELIVERY SYSTEMS
The tobacco industry is developing and marketing newer electronic nicotine
delivery systems such as “heat-not-burn” (HNB) tobacco products. An example
is Philip Morris Products S.A.’s product, IQOS (I-Quit-Ordinary-Smoking),
which heats a modified tobacco cigarette without combustion. (Philip Morris
Products S.A. is a subsidiary of Philip Morris International, Inc, [PMI].) As of
May 2018, IQOS is sold in over 37 countries, including Japan, the United
Kingdom, and Canada (141,142). Around that same time, IQOS had a 16.8%
share in Japan’s overall tobacco market, the largest share in any country where it
is marketed (142). In an effort to expand sales to the United States, Philip Morris
Products S.A. filed a modified risk tobacco product (MRTP) application in
December 2016 (143,144). Studies by Philip Morris Products S.A. found that
IQOS substantially reduced yields of hazardous and potentially hazardous
constituents (HPHCs) compared to 3R4F reference cigarettes (145,146). On
switching from conventional cigarettes to IQOS, biomarkers of toxicants fell
significantly (90% reduction) (147).
Since HNB products are marketed as heating but not combusting tobacco,
there are concerns that these products will be perceived as less harmful than
combustible cigarettes and that the products will be used to evade smoke-free air
laws. Toxic substances can be generated at lower temperatures than required for
combustion (including incomplete combustion/pyrolysis and thermogenic
degradation). At the time of publication of this text, the first independent study
(non-PMI, noncompetitors) of HNB was published (148). Eight VOCs including
acrolein, benzaldehyde, formaldehyde, and isovaleraldehyde were quantified in
IQOS emissions; these four VOCs were at levels of 41%-82% of levels released
by conventional cigarettes. Carbon monoxide was also released but at lower
levels than conventional cigarettes. Nicotine levels were 84% of those from
conventional cigarettes. Of particular concern was that IQOS also released 13
PAHs (almost all of which were vastly lower in amount compared to
conventional cigarettes); acenaphthene was released at levels 295% of those
formed from conventional cigarettes. This compound is not known to be a
carcinogen and implications for health are not known. The presence of PAHs in
IQOS emissions is indicative of some degree of pyrolysis/combustion, contrary
to current marketing by PMI and affiliates.
OTHER SUBSTANCE USE WITH E-

CIGARETTES
Vaporizers that heat cannabis without combustion, such as commercially
available tabletop vaporizers (eg, Volcano) and portable, pocket vaporizers (Pax
by Ploom), were used for cannabis vaping even before the popularization of
nicotine e-cigarettes. However, the emergence and pervasiveness of e-cigarettes
led to heightened concerns about the use of e-cigarettes to vape illicit drugs such
as cannabis (149). For example, people can potentially modify the e-cigarette
refill e-liquids with cannabinoids for use in tank e-cigarettes. However, due to
the poor solubility of tetrahydrocannabinol (THC) extracts and butane hashish
oil in commercial liquid refills, especially those high in glycerin content, people
who use e-cigarettes may find it challenging to vape cannabis in tank e-cigarettes
designed for use with nicotine e-liquids (150). The viscous formulation does not
flow readily into the atomizer where it can be vaporized. “Dabbing” wax infused
with THC directly onto the heating coils of rebuildable dripping atomizers may
be a more effective method of vaping cannabis using e-cigarettes.
While e-cigarette design is not optimized for delivery of drugs such as
cannabis, reports confirm that they are being used for this reason. An anonymous
survey of high school students in Connecticut revealed that 18.0% of students
who had tried e-cigarettes, 18.4% of those who had tried cannabis, and 26.5% of
dual e-cigarette/cannabis users had used e-cigarettes to vaporize cannabis (151).
The main forms of cannabis used by the students were hash oil, THC-infused
wax, and dried cannabis leaves. Studies also suggest that adults who use e-
cigarettes are vaporizing cannabis using e-cigarettes. No studies have
characterized THC intake, pharmacokinetics, and effects from vaping cannabis
and other illicit drugs with e-cigarettes. Other illicit drugs can also be delivered
via e-cigarettes, including a new designer drug “flakka” (a synthetic
amphetamine-like cathinone) (152). E-cigarettes have been known to be used to
deliver gamma butyrolactone among club patrons (153).
REGULATION OF E-CIGARETTES
The Family Smoking Prevention and Tobacco Control Act, signed into law on
June 22, 2009, gave the U.S. Food and Drug Administration authority over
tobacco products. In May 2016, the FDA Deeming Rule extended its authority to
e-cigarettes, cigars, hookah tobacco, and pipe tobacco (154). The rule stated
specifically that e-cigarettes were considered tobacco products and subject to
FDA regulation. The regulation of e-cigarettes includes e-liquids, atomizers,
batteries, delivery devices, and software. The rule required that manufacturers of
all products covered by the new regulations apply for marketing authorization,
unless the product was on the market as of February 15, 2007. Thus, the vast
majority of e-cigarettes require such authorization. There has been considerable
controversy about this rule, since, for most e-cigarette manufacturers, it would
be financially difficult or impossible to submit the necessary product information
to gain a modified tobacco product approval. It has been argued that such a rule
favors the large tobacco companies who have the financial resources to develop
and test e-cigarette products and that the independent e-cigarette manufacturers
and sellers, some of whom advocate for stopping smoking of conventional
cigarettes, would be forced out of business. At the time of the writing of this
chapter (July 2017), the FDA announced a delay in premarket tobacco product
application (PMTA) submission deadline from 2018 to 2022, thus allowing
products that were on the market as of August 8, 2016, to remain.
Given the potential health risks associated with e-cigarettes, including
uptake by youth, we recommend the following policy approach to e-cigarettes
(1,140):
Include e-cigarettes in smoke-free air laws; prohibit use of e-cigarettes in

any location where smoking of conventional cigarettes are prohibited.
Prohibit the sale of e-cigarettes to minors or anyone who cannot legally
purchase cigarettes.
Prohibit co-branding e-cigarettes with conventional cigarettes in ways that
promote dual use.
Ensure that e-cigarettes are subjected to the same level of restrictions that
apply to conventional cigarettes such as no television or radio advertising.
Prohibit marketing claims that e-cigarettes are effective tobacco/nicotine
treatment aids until the manufacturer provides sufficient evidence of
efficacy.It is important that the relevant government agency, such as the
FDA in the United States, monitor whether e-cigarettes are used to deliver
potentially addictive or harmful drugs other than nicotine.
All health claims associated with the e-cigarette products should be
reviewed and approved by regulatory agencies to scientific and regulatory
standards.
Product ingredients, components, and functioning should be regulated for
safety concerns.
ACKNOWLEDGMENTS
We thank Mr. Newton Addo-Otoo for editorial assistance. This chapter was
supported in part by grant number 1P50CA180890-02S1 from the National
Cancer Institute and Food and Drug Administration (FDA) Center for Tobacco
Products (CTP) and grant number 3R01DA039264 from the National Institute
on Drug Abuse and FDA CTP. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National
Institutes of Health (NIH) or the FDA.
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CHAPTER 21
Novel Psychoactive Substances: Their
Recognition, Pharmacology, and
Treatment
Kathryn Hawk, Barbara M. Kirrane and Gail D’Onofrio
CHAPTER OUTLINE
Treatment
Specific Examples of NPS
Nonpharmaceutical Fentanyl Analogues
Kratom
Krokodil
Salvia Divinorum
Identifying and Accessing Information on Newly Emerging and Novel
Psychoactive Substances
New synthetic drugs have increased at an alarming rate over the past several
years. While classic illicit substances such as cocaine and heroin were
traditionally agents of concern and regulation, the development of “novel
psychoactive substances” (NPS) or designer drugs created in clandestine
laboratories has been on the rise since the late 1970s. Typically, these drugs are
designed to mimic already existing substances such as cannabis, amphetamines,
or opioids and are manufactured specifically to circumvent laws related to the
sale and trafficking of controlled substances (1). The designation of NPS
includes synthetic cannabimimetics, synthetic cathinones, phenylethylamines,
piperazines, ketamine- and phencyclidine-type substances, tryptamines,
benzofurans, and synthetic opioids (2,3). Two of the better understood novel
drug categories include synthetic cathinones or “bath salts,” which are
derivatives of cathinone, a naturally occurring amphetamine analogue found in
the leaves of the Catha edulis plant, and synthetic cannabinoids, marketed as
Spice and K-2, that bind to cannabinoid receptors (1,4–6). Another category of
NPS includes nonpharmaceutical synthetic opioids such as acetyl fentanyl,
acrylfentanyl,3-methyl fentanyl (“China white”), butyrfentanyl, U-47700, and
carfentanil, which bind μ-receptors and have been reported to be between 15 and
10,000 times more potent than morphine (7–12). Little is known about the
mechanisms of action, pharmacological effects, and toxicological profile for
many other NPS, although specific details for “kratom,” “krokodil,” and salvia
are explored later in this chapter, and resources with information on NPS are
constantly being updated (1). More than 100 new substances were newly
reported to the European Union Early Warning System in 2015, bringing the
total of new NPS monitored by the European Monitoring Centre for Drugs and
Drug Addiction (EMCDDA) to more than 560 substances (13).
Some types of NPS are frequently promoted as “legal highs” and are easily
accessible in gas stations, convenience stores, “head shops,” and the Internet.
These substances are a particular concern for teenagers and young adults as they
are easily available and affordable, often packaged in colorful wrappers that do
not appear dangerous and are typically given fun, catchy names to draw attention
(13,14). They are sold as “legal highs,” “herbal highs,” “bath salts,” “plant
food,” “insect repellent,” “research chemicals,” and “air fresheners,” with
disclaimers that they are “not for human consumption” or “for research purposes
only” to circumvent regulation and controlled substances legislation (3,15).
Increased availability is just one of many potential facilitators of designer
drug use. NPS are largely undetectable using traditional methods for drug
screening, which may be a perceived benefit for individuals who anticipate
monitoring for illicit substance use. Others may be drawn to the rush of
“edgework” or the concept of pioneering and experimenting with substances
about which little is known (16). Importantly, NPS use is not always intentional,
as there have been a number of reports of designer drugs, including high-potency
fentanyl and analogues or other novel synthetic opioids such as U-47700
(“Pink”), detected in counterfeit black market prescription opioids and other
traditional illicitly used drugs such as heroin and cocaine (17–19).
Designer drugs are typically created when clandestine chemists modify the
structure of an existing drug, for example, adding a methyl group to the
compound, thereby creating an analog drug with similar properties, but not
necessarily subject to regulation (20). Legislative attempts both within and
outside of the United States, including the Federal Synthetic Drug Abuse
Prevention Act of 2012, have been passed in attempt to regulate the sale and use
of specific substances, with limited impact given the targeted development of
novel compounds specifically developed to skirt controlled substance regulations
(13,15,21). The EMCDDA has been following the development of hundreds of
new compounds since 2010, with more than 50% of the 560 substances
categorized as NPS having been identified since 2013 (3,13).
TREATMENT
Some people may be falsely reassured by the legal status of a number of these
NPS, not realizing that they have been linked to a variety of life-threatening
adverse events and have been implicated as the cause of numerous violent acts
(5,14,22–24). Epidemiological and US poison control center data suggest that
newer substances specifically targeted to skirt attempts at regulation are
increasingly toxic, with a 330% increase in calls to US poison control centers
related to synthetic cannabinoids between January and May 2015 (15,21,25). In
New York City, more than 4500 emergency department visits related to synthetic
cannabinoids were reported between January and August of 2015, with 2300,
more than half, of those visits occurring in July and August (26).
Different chemical structures ultimately mean different physiological effects,
and with no oversight or regulation in the production of these substances, the
resulting clinical picture can show wide variation across doses and individuals
even when individuals use the same amount of substance with the same label
(20,27). Acute intoxication with synthetic cathinones and synthetic cannabinoids
predominantly presents clinically with a sympathomimetic toxidrome, which
often includes tachycardia, hypertension, tachypnea, hyperthermia, agitation,
tremors, and/or seizures, although somnolence and hypotension have also been
reported (21,28,29). Synthetic cannabinoids have been associated with
nephrotoxicity, rhabdomyolysis, acute psychosis, and cardiac arrest, and
synthetic cathinones have been associated with acute psychosis, hallucinations,
paranoia, suicidality, and respiratory depression (21,24,28,30–32). Daily use of
synthetic cannabinoids has been associated with the development of a profound
withdrawal syndrome, which can include seizures, tachycardia, chest pain,
palpitations, anxiety, insomnia, diaphoresis, and anorexia and is managed by the
administration of benzodiazepines and second-generation antipsychotics (21).
Acute clinical care for patients with toxicity related to NPS ingestion can be
challenging as a wide variety of toxicological effects have been reported, and
batch to batch variability in potency, chemical composition, and adulterants may
limit the utility of patient-reported substance use history. Toxicologists and
emergency medicine physicians have traditionally focused on treating the
poisoned or intoxicated patient based on the clinical presentation and
characteristics rather than based on the specific poison or drug (29). Based on
the clinical presentation, including toxidrome and the best available history,
emergency care frequently includes supportive care, including intravenous
fluids; electrolyte repletion; evaluation for end-organ damage to the kidneys,
lungs, heart, and brain; treatment with benzodiazepines and antipsychotics as
needed; and observation. Naloxone administration should be considered for
patients presenting with the opioid toxidrome of miosis, respiratory depression,
and depressed mental status, even if a clear history of opioid use is not obtained,
and high-dose naloxone should be considered if clinically indicated or if there is
a suspicion for fentanyl or high-potency fentanyl analogues (18).
In the United States, poison control centers provide 24 hours per day, 7 days
per week access to trained toxicologists who are available to answer questions
and provide consultations for clinical management and can be reached by calling
(800)-222-1222.
SPECIFIC EXAMPLES OF NPS

See Chapters 15, 12, and 11 for more information about synthetic cannabinoids,
cathinones, and opioids, respectively.
NONPHARMACEUTICAL FENTANYL
ANALOGUES
History
Fentanyl is a short-acting opioid with 50-100 times the potency of morphine. It
was initially synthesized in 1960 by Janssen Pharmaceutica as part of an effort to
identify anesthetics with a more favorable safety profile than what was currently
available (33). The synthesis of multiple analogues for pharmaceutical use,
including sufentanil and alfentanil, soon followed. Although nonmedical use of
pharmaceutical fentanyl and fentanyl analogues (fentanyls) has been reported,
surveillance data suggest that increases in fentanyl-involved fatalities are related
to illicitly manufactured fentanyls produced by clandestine laboratories primarily
outside of the United States (34–36). A CDC analysis of 27 states with consistent
death certificate reporting of substances involved in opioid overdoses found a
high degree of correlation (r = 0.95) between synthetic opioid-related deaths and
increased fentanyl seizures reported to the National Forensic Laboratory
Information System (NFLIS) (36). Notably, no changes in fentanyl prescribing
rates were observed (36). Between 2013 and 2014, the Drug Enforcement
Administration (DEA) reported a 354% increase in fentanyl-related submissions
to the NFLIS and identified at least 15 unique fentanyl-related compounds in
seized samples (35). Fentanyls associated with numerous regional outbreaks of
fatal overdose include α-methyl fentanyl, 3-methyl fentanyl, acetyl fentanyl,
carfentanil, butyrylfentanyl, ocfentanil, and furanylfentanyl (12,18,29,37–39).
Previously, regional outbreaks of exposure to fentanyls were largely thought to
be related to contamination of the heroin supply, although recent reports
highlight the existence of a specific market for fentanyls with increasing reports
of intentional use, sometimes purchased over the Internet or Dark Web (9,38,40).
Pharmacology
Fentanyl is a synthetic mu-opioid receptor agonist, with a potency 50-100 times
greater than morphine and 30-50 times greater than heroin (35). Fentanyl
analogues range in potency from acetyl fentanyl, 15 times more potent than
morphine, to carfentanil, 10,000 times more potent than morphine (12,38).
Fentanyl is well absorbed transmucosally, accounting for the lozenge and
lollipop routes of administration for pharmaceutical fentanyl, and is available in
a transdermal delivery system, Duragesic (29). In 2015, the DEA issued
warnings to law enforcement and first responders about the possibility of
fentanyl being absorbed through the skin and accidental inhalation of airborne
powder (35). The American College of Medical Toxicology and American
Academy of Clinical Toxicology acknowledged in 2017 the possibility of
weaponized aerosolized fentanyl toxicity but concluded that incidental dermal
absorption or inhalation is unlikely to cause opioid toxicity to first responders
and law enforcement officers exposed during routine civic service (41).
Although unconfirmed, based on clinical reports from responding physicians,
there is high suspicion that the gas used to subdue Chechen rebels holding 800
hostages at a Moscow Theater in 2002 contained aerosolized carfentanil or other
high-potency fentanyl analogs (29,42).
Clinical Implications
Clinically, fentanyl is used in general and regional anesthesia and in the
management of chronic and postoperative pain (38). Recreationally, fentanyls
are used for their euphoric effects. Fentanyls cause a typical opioid toxidrome
with respiratory depression, miosis (constricted pupils), drowsiness and
euphoria, and, at high doses, respiratory arrest and pulmonary edema (38). The
most common side effects include nausea, dizziness, vomiting, fatigue,
headache, and constipation; repeated use leads to the development of tolerance
and physical dependence (29,38). Opioid overdose, the combination of
decreased respiratory rate, decreased mental status, and miosis, can be reversed
with the mu-opioid receptor antagonist naloxone, which can be administered via
intranasal, intramuscular, or intravenous routes. Fentanyl is not included in many
hospital urine toxicology screens, so exposure is often undetected. Like many
exposures, source identification may be delayed or never occur so clinical
presentation and patient toxidrome should guide acute management (18).
Legal Status
Fentanyl, alfentanil, sufentanil, remifentanil, and carfentanil are Schedule II
substances, while 3-methylfentanyl, α-methyl fentanyl, acetyl fentanyl, and
furanylfentanyl are categorized as Schedule I (43).
KRATOM
History
Kratom is a plant product derived from Mitragyna speciosa Korth, a leafy tree
that is a member of the coffee family and native to Southeast Asia, although it is
now cultivated elsewhere (44). Kratom was used in Thailand and Malaysia as
early as the 1800s by manual laborers for euphoria, stimulation, and analgesia
and to prevent withdrawal from opium (45). Traditionally, the kratom leaves are
chewed or brewed into a tea; they are rarely smoked. Today, kratom is widely
available on the Internet and specialty stores and can be found as capsules,
tablets, gum, dried leaf, or powder (44). Kratom has become increasingly
popular in the United States over the past several years given its wide
availability in stores and on the Internet along with its current legal status as an
unscheduled substance. It has also been referred to by slang names such as
thang, kakuam, thom, ketum, and biak (43). The number of calls to US poison
centers concerning reported exposures to kratom increased tenfold from 2010 to
2015 (46). Kratom is commonly used today to self-treat chronic pain, prevent
opioid withdrawal, and for its hallucinogenic effects, though other reported
beneficial effects include antipyretic, antihypertensive, antidiarrheal, anti-
inflammatory, and prolonging sexual intercourse (22,45).
Pharmacology
Although more than 40 different alkaloids have been isolated from kratom, the
primary one is the indole alkaloid mitragynine (47,48). Mitragynine is an agonist
of multiple receptors, including the opioid mu and delta receptors, as well as
postsynaptic alpha-adrenergic receptors, dopamine and serotonin receptors
(22,49). Mitragynine is reported to have a mu-opioid receptor potency ~10 times
that of morphine, a key reason why kratom is used to prevent opioid withdrawal.
The mitragynine content of kratom leaves is variable and may depend on
geographic location as well as season cultivated (50). A recent analysis of
multiple commercial kratom products found a substantially higher concentration
of 7-hydroxymitragynine than found in natural M. speciosa leaves, suggesting
the intentional adulteration of these products to increase addiction potential (44).
Kratom has dual properties that result in both stimulation and analgesia,
depending on the exposure dose. At low doses, kratom acts primarily as a
stimulant, producing a sympathomimetic toxidrome; at higher doses, effects are
predominantly consistent with an opioid toxidrome (50). Effects begin between 5
and 10 minutes after exposure and typically last for 1 hour (45). Symptoms of
acute intoxication reported to poison centers include tachycardia, agitation,
drowsiness, nausea, and hypertension (46). Published case reports have
associated kratom exposure with psychosis, seizures, coma, and death
(45,49,51,52). A withdrawal syndrome has been reported in individuals with
addiction and includes symptoms such as nausea, vomiting, diarrhea, insomnia,
hot flashes, and abdominal pain (53). There is no antidote for kratom, and the
treatment is primarily supportive.
Legal Status
Kratom is currently unscheduled by the DEA, and so is legal to cultivate, buy,
possess and sell. It is under consideration for a Schedule I classification and is
currently listed as a “drug and chemical of concern” (43).
KROKODIL
History
“Krokodil” is a name used for desomorphine, an injectable opioid derivative
created as a less expensive alternative to heroin. Krokodil first appeared on the
Russian drug market in 2003 as an epidemic and has been reported in many
European countries as well as the United States since that time (54,55). Its name
is derived from the word crocodile (krokodil in Russian) and refers to the scaly,
green-black ulcerated skin discoloration frequently seen in people with people
who use it regularly (56). Krokodil is easily synthesized in homes and
clandestine labs from codeine, which is available over the counter in Russia, and
combined with other easily available, low-cost chemicals such as hydrochloric
acid, red phosphorous, iodine, gasoline, or paint thinners (56). Due to its crude
production and lack of a purification process, the final product is typically
contaminated with high concentrations of corrosive chemical by-products
(54,57). Persons with any use of krokodil have experienced serious medical
problems.
Pharmacology
Desomorphine, the intended ingredient in krokodil production, is a morphine
analog and mu-opioid receptor agonist. Desomorphine has a potency of ~10
times that of morphine (54). The increased potency and more rapid onset of
action has been partially attributed to the replacement of an alcoholic hydroxyl
group with a hydrogen ion that increases the lipophilic properties of
desomorphine and facilitates transfer across the blood–brain barrier (58).
Clinical symptomatology resembles that of the opioid toxidrome. However,
additional significant damage occurs to the area of injection, which starts with
swelling and pain and progression to green-black discolored scaling and large-
scale necrotic ulceration (56). This ulceration can progress to involve the muscle
and surrounding tissue, and exposing the underlying bone. Furthermore,
complications such as meningitis, speech and motor impairments, multiorgan
injury, bacteremia, thrombophlebitis, venous ulcers, and skin eschar have been
reported (59–61). Krokodil appears to be more associated with severe skin
findings than other injectable drugs. These findings may be due to the
contamination of the chemicals used to manufacture krokodil, but the exact
mechanism remains unknown (57). Krokodil has been reported to be used with
tropicamide, a short-acting anticholinergic agent, which causes mydriasis,
conjunctival erythema, and an altered mental status, and a can cause a “zombie”-
like appearance in those with frequent use (62). Like other opioids, withdrawal
syndromes are possible with cessation of use. Treatment includes opioid
antagonism for acute intoxication and supportive care for skin and systemic
sequela.
Legal Status
Desomorphine is a Schedule I controlled substance in the United States (26).
SALVIA DIVINORUM
History
Salvia divinorum is a member of the mint family and endemic to a limited area
of the highlands of the Mexican Oaxaca state. Other names for Salvia divinorum
include “diviner’s sage,” “mystic sage,” “magic mint,” “Maria Pastora,” and
“Sally D” (63,64). Long recognized for its hallucinogenic properties, Mazatec
Indians ingest fresh leaves or leaf preparations to promote visions and
experiences for divinatory rituals, healing ceremonies and medicinal purposes
(64). Of the known salvia species, only S. divinorum is known to contain
salvinorin A, the component responsible for its hallucinogenic properties (22).
Since the late 1990s, salvia has had a surge in popularity due to its reputation as
a “legal high”, its wide availability on the Internet and in head shops, lack of
detection on drug screens as well as perceived safety (22). In the United States, it
is most commonly used in young adults aged 18 to 25 years (65).
Pharmacology
Use of Salvia divinorum produces vivid hallucinations. Salvinorin A is a highly
selective agonist of the kappa opioid receptor (50). Typically, stimulation of the
kappa opioid receptor results in hallucinations, diuresis, and spinal analgesia but
does not result in respiratory depression. Salvinorin A does not demonstrate
binding affinity for the serotonin 5-HT 2A receptor, which sharply distinguishes
this agent from other hallucinogens (50).
Classically, the plant is smoked or chewed. Effects are seen rapidly, often
between 30 seconds and 10 minutes depending on route of administration (45).
Hallucinations are intense and many people with exposure report visual
distortions of body images; out of body, dream-like experiences; and
synesthesias (66). Some individuals have reported dysphoria and frightening
hallucinations (22). Hallucinations are brief and typically dissipate within 30
minutes (45). Other symptoms include confusion, dizziness, flushed sensation,
and tachycardia (64,65). Treatment for salvia toxicity is primarily supportive.
Legal Status
Neither Salvia divinorum nor salvinorin A is currently controlled under the
Controlled Substances Act, although several states have regulated their use (43).
IDENTIFYING AND ACCESSING

INFORMATION ON NEWLY EMERGING
AND NOVEL PSYCHOACTIVE
SUBSTANCES
A variety of organizations conduct surveillance and collate information to
inform the public and clinicians and the development of public health and law
enforcement policy. In the United States, poison control centers collect national
surveillance data on drug exposures and provide toxicology support 24 hours per
day, 7 days per week for lay people and clinicians (1-800-222-1222). The United
States Drug Enforcement Agency (DEA) enforces the controlled substance laws
and regulations of the United States, collaborates with local law enforcement and
health professionals regarding seizures and poisonings, and maintains the
National Forensic Laboratory Information System (NFLIS) to collect, analyze,
and disseminate drug intelligence information (67). The European Monitoring
Centre for Drugs and Drug Addiction (EMCDDA) conducts similar data
collection, registration and analysis of both licit and illicit substances, including
wastewater and seized material chemical analysis, and analysis of global market
and trade patterns for the European Union. The U.S. Substance Abuse and
Mental Health Services Administration and the National Institutes of Health
fund periodic large-scale, population-based epidemiological studies (eg, National
Survey on Drug Use and Health, Monitoring the Future) that collect self-
reported data on substance use that are available to the public. Local and state
health departments, local law enforcement agencies, and medical examiners may
also be a source of additional information.
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SECTION 3
Diagnosis, Assessment, and Early

Intervention
CHAPTER 22
Screening and Brief Intervention
Suena H. Massey, Nicole A. Hayes, Michael F. Fleming
and Aleksandra E. Zgierska
CHAPTER OUTLINE
Introduction
National Recommendations on the Implementation of Unhealthy Substance
Use Screening and Treatment in Medical Care Settings
Screening and Brief Intervention: Clinical Guidelines
Current Evidence on Screening and Brief Intervention: A Brief Summary
Systematic Reviews and Meta-analyses of Screening and Brief
Interventions for Unhealthy Alcohol Use
Individual Studies of Screening and Brief Intervention for Unhealthy
Alcohol Use
Individual Studies of Screening and Brief Intervention for Unhealthy Drug
Use
Summary
INTRODUCTION
Based on recent estimates from nationally representative epidemiologic samples
in the United States, past year and lifetime prevalence of alcohol use disorders
(AUDs) defined by DSM-V criteria are 13.9% and 29.1%, respectively (1).
Rates are considerably higher among individuals with mental health problems
and those presenting with trauma in emergency settings. Prevalence rates of 12-
month and lifetime nonalcohol drug use disorders are estimated at 3.9% and
9.9%, respectively (2) with prescription opioid misuse cited as a “national
epidemic”(3). Thus, a sizeable proportion of patients presenting to primary care
and hospital settings have or have had problems with alcohol and other drugs.
On any given day, physicians provide medical care to patients with unhealthy
alcohol or drug use and related medical symptoms or conditions including liver
failure, hypertension, obesity, glucose intolerance, memory loss, and a variety of
mental health conditions are directly related to unhealthy alcohol use.
Adding to the complexity of the problem is the challenge of engaging
patients, and also their physicians, in systematic evidence-based solutions.
Evidence suggests that patients actually prefer to address their alcohol use with
their own physicians rather than receiving treatment from Alcoholics
Anonymous or specialty addiction treatment (4). In this way, screening and brief
intervention (SBI) has the potential to be a suitable solution—it was designed
specifically for implementation into primary care settings and has been shown to
reduce self-reported excessive alcohol use in patients without AUD (5) with
efficacy for nonalcohol drug use and disorders yet to be established. A unique
aspect of SBI is its harm reduction paradigm that emphasizes reduction in use or
abstinence to reduce negative consequences most important to patients rather
than the goal of abstinence due to admitted “powerlessness over alcohol”
foundational to Alcoholics Anonymous and other 12-step programs.
Unfortunately, widespread implementation of SBI and acceptability by
physicians has been disappointing leading in part to investigations on SBI
delivered by smartphone and online platforms (6).
NATIONAL RECOMMENDATIONS ON
THE IMPLEMENTATION OF
UNHEALTHY SUBSTANCE USE
SCREENING AND TREATMENT IN
MEDICAL CARE SETTINGS
Over the past almost five decades, research has demonstrated the potential
benefits of SBI as a brief behavioral therapy for tobacco and unhealthy alcohol
use in a variety of public health and clinical settings. Based on this evidence,
recent years have witnessed structured efforts to disseminate SBI for alcohol and
tobacco use into clinical practice. SBI for drug use, in particular, cannabis use,
has been less emphasized in light of discrepancies in legalization status of
cannabis among states and lack of proven efficacy.
The U.S. Preventive Services Task Force (USPSTF) recommends routine SBI
to reduce alcohol “misuse” by adults, including pregnant women in primary care
settings (grade B) (7) and strongly recommends that clinicians screen all adults,
including pregnant women, for tobacco use and provide tobacco treatment
interventions for people who use tobacco (grade A) (8). The USPSTF concludes
that the evidence is insufficient to recommend for or against routine SBI to
prevent or reduce alcohol misuse or tobacco use among children and
adolescents. The USPSTF has found insufficient evidence to recommend
universal SBI for illicit drug use (9).
A number of professional medical organizations have adopted policies
calling on their members to be knowledgeable, trained, and involved in all
phases of prevention and SBI for tobacco and unhealthy alcohol use. For
example, the ACS Committee on Trauma requires screening of all level I and
level II trauma patients for unhealthy alcohol use as well as providing BI for
those patients who screen positive in level I trauma centers (10). These
recommendations have also been endorsed by the National Institute on Alcohol
Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA),
the Substance Abuse and Mental Health Services Administration (SAMHSA),
and the National Quality Forum (NQF) (for alcohol), a voluntary consensus
evidence-based standard-setting organization. While organizations recommend
screening for alcohol and tobacco use in adults and adolescents. The specific age
of onset of such services is less well defined, though. The NQF recommends
alcohol and tobacco SBI services for patients 10 years of age or older during
new patient encounters and at least annually (11). The NIAAA recommends
alcohol screening starting even earlier, at age 9, and provides a clear algorithm
for youth SBI in its Guide for Youth (12). NIDA tools have been developed for
drug misuse SBI in adults (13).
Less unified recommendations regarding screening for marijuana use reflect
an evolving view of marijuana that varies by state—advocacy for further
research into the overall safety and health effects of recreational marijuana use is
universal (14). For example, the American Academy of Family Physicians
(AAFP) opposes the recreational use of marijuana, while supporting
decriminalization of the possession and personal use of marijuana (15). The
American Society of Addiction Medicine (ASAM) “opposes proposals to
legalize marijuana anywhere in the United States …. The analyses on the
possible outcomes—both intended and unintended—of the state-based marijuana
legalization proposals … suggest that risks are unacceptable”.
Implementation of these recommendations has been modest though adoption
of billing codes by the AMA and the Centers for Medicare and Medicaid
Services for tobacco as well as alcohol/other drug use–structured SBI services
represents a step toward this goal (16). For example, Medicare waives
coinsurance, copayment, or deductible for the preventive services graded as A or
B by the USPSTF that include alcohol and tobacco SBI for adults and pregnant
women in primary care. Medicare also has specific regulations about the settings
of SBI delivery. It covers tobacco cessation SBI for both outpatient and inpatient
beneficiaries. It also covers annual screening for unhealthy alcohol use and—for
those who screen positive and are diagnosed with unhealthy use but not DSM-
IV–defined dependence—up to four brief face-to-face counseling interventions
in a 12-month period. Each intervention should be consistent with the Five A’s
approach (Ask, Advise, Assess, Assist, Arrange) and provided by a qualified
physician (general practice, family medicine, geriatrics, pediatrics, internal
medicine, or OB/GYN) or other recognized clinician in primary care settings
that, of note, exclude emergency departments or skilled nursing facilities.
Medicare does not identify specific tools to screen for or diagnose unhealthy
alcohol use; they can be chosen, as appropriate, by the clinician (17).
SCREENING AND BRIEF

INTERVENTION: CLINICAL
GUIDELINES
“If you aren’t already doing so, we encourage you to incorporate alcohol
screening and intervention into your practice. You’re in a prime position to make
a difference.”
These first lines of the booklet “Helping Patients Who Drink Too Much: A
Clinician’s Guide” summarize the current NIAAA guidelines on alcohol SBI in
primary care and mental health settings (18). While this guide provides an
algorithm for a step-by-step approach to alcohol SBI for adults, another guide
recently released by the NIAAA addresses nuances of alcohol SBI delivery in
youth (19). Both guides are available in both extended (yet concise) and pocket
(one small booklet) sizes. NIDA’s guide incorporates SBI for alcohol, tobacco,
and other drugs in one document (13).
Clinical Approach to SBI Services in Primary

Care Settings
A commonly recommended framework for delivery of SBI, particularly for
tobacco use, is the Five A’s (Ask, Advise, Assess, Assist, Arrange):
Ask refers to screening and assessment of the risk level: “Screen, then
intervene.” Intervention may then include all remaining “A’s” and is
tailored to the screening results and determined risk level.
Advise means direct personal advice about substance use. The goal of the
clinician’s advice is for the patients to hear clearly that a change in their
behavior is recommended as based on medical concerns (review results
with the patient), and to learn about their personal substance use and its
effects on health (provide advice). Presentation of the facts in an objective
way, using strong and personalized language, by a knowledgeable and
trusted professional, has been shown to facilitate change.
Assess refers to evaluating the severity of the patient’s problem and the
patient’s willingness (“readiness”) to change the unhealthy behavior
(reduction of use or quitting), after hearing the clinician’s advice. If the
patient is not willing to change his or her substance use, the clinician should
restate the substance use–related health concerns, reaffirm a willingness to
help when the patient is ready, and encourage the patient to reflect about
perceived “benefits” of continued use versus decreasing or stopping use and
barriers to change.
Assist involves helping the agreeable patient develop the treatment plan
following the patient’s personal goals. Using behavior change techniques
(eg, motivational interviewing [MI]), the clinician should aid the patient in
achieving agreed-upon goals and acquiring the appropriate skills,
confidence, and social/environmental support. It is helpful if the plan
describes in concrete terms the specific steps the patient elects to take to
reduce/quit drinking, for example, the maximum number of drinks per day
or week and how to prevent and manage high-risk situations or establish a
support network. Starting with “small steps” while working toward a larger
goal (abstinence or safe use) may be most reasonable and achievable for
many patients.
Clinicians should also consider whether the patient would benefit from a medical
treatment for addiction, such as withdrawal management or pharmacotherapy, or
an additional assessment and therapy for potential comorbid physical or mental
health problems. All sexually active patients with unhealthy alcohol or drug use
—a risk factor for “risky behaviors”—should be counseled to practice safe sex
and offered HIV and other sexually transmitted disease testing. Patients
reporting any injection drug use should be encouraged to undergo HIV and
hepatitis B/C testing if they have not had it twice over a 6-month period
following the last injection.
Finally, Arrange refers to the consideration of a follow-up visit and

specialty referrals. A follow-up appointment should be arranged for all
patients who screened positive to provide ongoing assistance and adjust the
treatment plan as needed. Optimally, all patients should also receive
educational materials to take home.
All patients with a substance use disorder should be encouraged to see an
addiction specialist or to receive care for that disorder from any clinician able to
provide it, including their primary care clinician who could consider the
appropriateness of prescribing medication. Unfortunately, many patients will
decline, especially during this initial meeting, or not be able to successfully seek
such services (eg, too few treatment options, clinician with skills not available,
too far to the nearest center, incompatibility of treatment schedule with work
hours, inadequate insurance coverage). However, almost regardless of
geographical location, time of the day, or insurance coverage, many patients can,
if they wish to do so, engage in mutual help groups such as Alcoholics
Anonymous (AA) or Narcotics Anonymous (NA) or SMART Recovery. These
groups are not professional treatment, but for those with a disorder, they can
serve as a sober supportive social network. SAMHSA’s Treatment Facility
Locator (http://findtreatment.samhsa.gov) and NIDA’s National Drug Abuse
Treatment Clinical Trials Network List of Associated Community Treatment
Programs (www.drugabuse.gov/CTN/ctps.html) can help find drug and alcohol
treatment programs around the country. Primary care physicians can also
complete a certification (through, eg, an 8-hour Web-based training) in office-
based buprenorphine maintenance therapy for opioid use disorder to additionally
treat selected patients (http://buprenorphine.samhsa.gov/howto.html).
Follow-up visits allow clinicians to offer a continued support for the patient.
With patients who adhere to the set goals, clinicians should reinforce progress;
renegotiate treatment goals, if indicated; and encourage regular follow-up. At
each follow-up, patient progress should be documented (“Was the patient able to
meet and sustain his goals?”). Former “at-risk users” and any patients about
whom the clinician remains concerned should be rescreened annually. Those
remaining moderate or high risk should be reassessed at the next appointment.
Patients who have a substance use disorder need careful close monitoring for
follow-through with more intensive treatment, addiction treatment programs,
self-help groups, coordination of care with specialists, and treatment of
coexisting medical and mental health conditions. Patients who did not meet their
treatment goals should be additionally supported; they should be praised for
coming in and for courage to honestly report their situation. Clinicians should
acknowledge that change is difficult; reemphasize willingness to help; readdress
the impact of continued substance use; reevaluate the diagnosis, treatment goals,
and plan; consider engaging significant others; and schedule close follow-up.
SBI for Unhealthy Substance Use (Alcohol,

Drugs, Tobacco): Approaches
Unhealthy Substance Use Screening
In the context of guidelines discussed previously, a variety of screening tools of
varying length and SBI implementation options exist for unhealthy substance,
including drug, use in clinical practice. Smith and colleagues showed that a
single question, “How many times in the past year have you used an illegal drug
or used a prescription medication for nonmedical reasons?” accurately
identified drug use in primary care patients. A response of at least 1 time was
considered positive for unhealthy drug use. NIDA’s recommended approach
begins with an algorithm, the initial screen, the so-called Quick Screen,
representing Step 1 of SBI and consists of a single question about past year
substance use, adapted from the screening tool developed for adult primary care
patients (Table 22-1). Those answering “yes” to the initial screen (positive Quick
Screen) should then receive an in-depth assessment (Step 2) to allow
determination of the risk level (Step 3). Providing advice, and if needed, a brief
intervention (Step 4) completes the SBI process.
TABLE 22-1 “ASK”: Single-Question Initial Screen for

Substance Use (NIDA Quick Screen)
aPossible responses: “once or twice,” “monthly,” “weekly,” or “daily or almost daily.”

bHeavy drinking: five or more (for men) or four or more (for women) drinks in a day.
Negative Quick Screen (“never” response to all substances) does not require
further, more detailed evaluation (see Table 22-1). Those with a negative screen
(abstinence) should be praised, encouraged to continue healthy lifestyle choices,
and rescreened annually (“It is really good to hear you aren’t using drugs. That
is a very smart health choice”).
Positive Quick Screen warrants a more detailed evaluation though. In case of
alcohol (“yes” to heavy drinking) or tobacco (“yes” to any tobacco use), the
NIDA guide recommends proceeding with alcohol (13) or tobacco SBI and
provides links to the appropriate websites (see Table 22-1). Because any tobacco
use places a patient at risk, all tobacco users should receive strong, unambiguous
advice to quit (“Quitting tobacco is the most important thing you can do to
protect your health”) (20).
Regardless of the exact methods used, it is important for clinicians to assess
consequences of drug use and screen for drug use routinely and repeatedly to
avail opportunities for intervention and prevention.
Drug SBI
Assessment of Severity: At-Risk Use, or Disorder
Those with a positive screen for drugs (“yes” to any use) should complete the
NIDA-Modified ASSIST questionnaire (21), called NM-ASSIST, available as an
interactive Web-based (www.drugabuse.gov/nmassist) or “full text” survey
(www.drugabuse.gov/sites/default/files/pdf/nmassist.pdf); the NIDA approach
favors NM-ASSIST, but screening for and severity assessment of unhealthy drug
use can be accomplished using other tools.
The eight-question NM-ASSIST inquires about the type of drugs, frequency
of their use, and symptoms suggestive of a disorder. Its total score, the so-called
substance involvement score, determines the level of risk associated with illicit
or nonmedical prescription drug use (0-3 points, lower; 4-26 points, moderate;
and 27 + points, high risk, consistent with moderate to severe disorder). If more
than one drug is reported, the patient receives a score for each substance
endorsed (the NM-ASSIST questions are “repeated” for each reported drug),
rather than a single cumulative score. Therefore, the patient’s risk level may
differ from drug to drug. In addition to its “scored” questions, the NM-ASSIST
also includes a question about injection drug use.
Clinicians should use clinical judgment to decide whether/when to deliver an
intervention for drug use (especially if the risk level is assessed to be “lower”).
The screen is only one indicator of a patient’s potential drug use risk. In case of
an elevated “risk level” identified for more than one drug (substance), a decision
about which substance to address first also needs to be clinically driven; in
general, focusing intervention on the substance with the “highest risk” or the
patient’s expressed greatest “motivation to change” may produce best results,
though an approach to addressing all substances simultaneously can also be
appropriate. Similarly, a cautious and clinically driven approach relates to the
urine toxicology results, which represent only one of the multiple pieces of the
clinical puzzle; the NIDA guide has a separate appendix with the tips on biologic
sample testing. Addition of biomarker testing, such as urine toxicology assays
for drugs or serum carbohydrate–deficient transferrin level for drinking, may be
beneficial in selected patients, particularly for follow-up monitoring (22).
Alcohol SBI for Adults

Adult Alcohol Screening
Consistent with the NIDA algorithm (described above), the NIAAA recommends
a single question (see Table 22-1) about the presence of heavy drinking as an
initial screen: “How many times in the past year have you had five or more (for
men) or four or more (for women) drinks in a day?” (18,19). This single
question is sensitive and specific for detecting unhealthy alcohol use in primary
care(16,23) and to a lesser degree, inpatient settings (24). The NIAAA suggests
an optional prescreening question about any alcohol use (“Do you sometimes
drink beer, wine, or other alcoholic beverages?”) can help “ease” the patient into
the more detailed screening should the patient answer “yes.” During this
conversation, it is important to discuss with the patient what constitutes a single
or “standard” drink (Table 22-2); presenting the patient with a chart of “standard
drinks”—as the one available in the NIAAA’s Clinician’s Guide or online
(www.RethinkingDrinking.niaaa.nih.gov)—can be very useful. This latter site
can additionally help the patients screen themselves for unhealthy alcohol use
(5).
TABLE 22-2 Maximum (Low-Risk) Drinking Limits for

Adults
One standard drink is equivalent to 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof spirits.
aExceeded daily limit: heavy drinking.
bExceeded daily or weekly limit: at-risk drinking.
With the endorsement of not drinking any alcohol or not engaging in any heavy
drinking in the past year, the screen is negative and completed. Any heavy
drinking in the past year constitutes a positive screen. Clinicians may decide
though to recommend lower “drinking limits” (perhaps in the elderly) or even
abstinence for patients taking medications that may interact with alcohol (eg,
benzodiazepines or opioids), who engage in certain activities (eg, driving), or
who have a medical condition worsened by alcohol. For pregnant women,
abstinence is the recommended healthiest choice.
A positive screen (heavy drinking or drinking above the clinician-
recommended limits in the past year) warrants further inquiry about the alcohol
use pattern and impact. At this point, we should determine the patient’s usual
weekly alcohol consumption by asking questions about frequency and quantity
(“On average, how many days a week do you have an alcoholic drink?” and “On
a typical drinking day, how many drinks do you have?”). These two questions
enable estimation of the number of drinks per week, which, if it exceeds weekly
limits (see Table 22-2), increases the level of concern for unhealthy alcohol use.
All the gathered numbers should be recorded in the patient’s chart; they can be
used later for a targeted counseling and to help monitor treatment progress.
A notable alternative approach to the single screening question is
administration of the three questions about consumption from the Alcohol Use
Disorders Identification Test (AUDIT) developed by the World Health
Organization (25) or the AUDIT-C (26). These three questions have been
associated with high predictive validity regarding unhealthy alcohol use in
Veterans Administration populations (27) and college students (28).
Assessment of Severity in Adults: At-Risk Drinking and

Alcohol Use Disorder
While the NIAAA’s Clinician’s Guide and its associated materials use DSM-IV
terminology of alcohol “abuse and dependence,” it remains an easily accessible
and easy-to-use method for discerning level of risk and appropriate treatment
tailored to this in routine day-to-day clinical practice. Specifically, patients who
exceed recommended drinking limits or the questionnaire cutoffs but do not
meet the criteria for AUDs are categorized as having “at-risk drinking,” a risk
factor for the development of AUDs and other health consequences.
Determination of risk by clinicians or their patients using respective versions of
the Clinician’s Guide materials can be useful for both parties. Distinguishing
between “at-risk drinking” and disorder is clinically relevant because it
determines the appropriate clinical recommendation. As discussed below in the
section on evidence, those classified as “at-risk drinkers” but do not meet criteria
for AUD are most likely to benefit from BI alone, while patients meeting criteria
for AUDs are less likely to do well without more intensive intervention.
Alcohol Brief Intervention in Adults

A brief intervention is appropriate for patients meeting criteria for unhealthy
drinking. With the patient’s agreement, the clinician should provide, in an
empathic and nonconfrontational manner, an objective assessment of drinking
and its consequences (information about personal health harms, and possible
benefits of cutting down or quitting) as well as clear, specific, and personalized
behavior change advice: “You’re drinking more than what is medically safe. I
strongly recommend that you cut down on your drinking.” “I believe that your
drinking is a serious risk to your health and I strongly recommend that you quit
drinking.” “As your physician, I am willing to help you reduce or quit drinking.”
Abstinence can produce better treatment outcomes than drinking reduction in
people with AUDs, especially those with advanced disease. Abstinence may also
be recommended as a primary treatment goal for patients with specific comorbid
medical or psychiatric conditions. However, for many people who should, but
may not be willing to abstain, drinking reduction may be more acceptable. Even
modest reductions in drinking can result in decreased alcohol-related harms. For
some patients, cutting down from daily drinking to 3 days a week may be
appropriate. For college students, cutting down from 12-15 drinks to 5-6 drinks
on a weekend night may reduce the risk for significant harm and convince the
student to begin the longer-term process of cutting back even further to lower the
risk level.
SBI for Youth

Substance Use in Youth: General Considerations
In spite of the fact that the legal drinking age is 21 years in the United States,
many youth start drinking earlier in life: One in three children had an alcoholic
beverage by the end of 8th grade, with half of them reporting getting intoxicated
(29). Drinking contributes to the top three causes of death among adolescents:
unintentional injury (eg, motor vehicle accidents), homicide, and suicide (30).
Evidence shows that drinking at a younger age increases the risk of developing
addiction and alcohol-related harms, which include serious consequences such as
death, injuries, motor vehicle crashes, and high-risk behaviors, as well as mental
and physical health disorders. Mental health problems most likely to co-occur
with AUDs include depression and suicide, anxiety, attention deficit
hyperactivity, conduct, schizophrenia, and bulimia disorders. Associated
physical health conditions include trauma sequelae, sleep, eating or
gastrointestinal problems, sexually transmitted infections (STIs) or unintended
pregnancy, and liver enzyme abnormalities.
Patterns of substance use in the community have influence on the youth’s
substance use. Permissive parental attitudes toward substance use and having
friends or family members who use alcohol, tobacco, or drugs are strong
predictors of substance use by youth. Parental monitoring and presence of clear
household rules about substance use are protecting factors against the youth’s
substance use (29).
Although the guidelines by the USPSTF state that existing evidence is
insufficient to recommend routine screening for unhealthy substance use in
youth, new research lends support for effectiveness of SBI for adolescents (31),
and most professional organizations, including the American Academy of
Pediatrics (AAP), the AAFP, the NIAAA, the NIDA, and the NQF, recommend
implementing SBI in youth.
In 2011, the NIAAA, in collaboration with the AAP, released a guide for
practitioners describing the rationale for and an approach to alcohol SBI for
youth (32). According to this guide, all children and youth between ages 9 and
18 years should be screened for alcohol use as part of an annual examination or
acute care visit or when seeing patients who
Have not been seen recently

Are likely to drink (eg, youth who use tobacco)
Have mental health problems known to co-occur with substance use
disorders
Have physical health conditions that might be alcohol related
Engage in high-risk behaviors (eg, have STIs or are pregnant)
Show substantial negative behaviors
Confidentiality and Parental Involvement
Screening minors for substance use and related disorders inevitably brings to
light the issue of confidentiality and parental involvement. Setting the stage in
advance for the scope and extent of confidentiality is very helpful. Optimally,
clinicians would share with the patient and the parents all the details about
confidentiality policies and disclosure provisions in advance, best starting at 7-
or 8-year-old well-child visits, or at least prior to the screening. With all
adolescents who use substances, the clinician should inquire about parental
awareness, and seek the patient’s permission to speak to the parents (or
guardians) or, at least, encourage the patient to discuss substance use with the
parents.
In general, the discussion about and treatment for the minor’s substance use
can usually be kept confidential if the minor wishes to do so; preserving
confidentiality may help strengthen the trust and treatment alliance between the
clinician and the minor. Although most medical organizations and laws support
the ability of clinicians to provide confidential care for minors in relation to
substance use, it is important to be aware of specific laws governing each state.
Information about minor consent laws can be obtained from the state medical
societies or the Center for Adolescent Health and the Law (www.cahl.org).
There are circumstances, though, when a clinician should consider breaking
confidentiality and engage the parents to ensure safety, for example, the presence
of “acute danger signs” (see below in assessment of severity in youth), a need
for referral for further treatment, or negative health consequences related to
substance use. The NIAAA guide also suggests engaging parents, even against
the minor’s wishes, for any alcohol use by elementary school kids, alcohol-
related mild problems in middle school, or significant problems in high school
students. In general, the clinicians should apply their best medical judgment,
together with the state’s laws, to decide whether breaking confidentiality is
warranted. Confidentiality can be unintentionally compromised if, for example,
the diagnostic codes that may reveal the nature of the adolescent’s problems are
included in “explanation of benefits” sent to parents by the insurance company
or when a follow-up visit is scheduled for “substance abuse”; these aspects of
care require a consideration in advance (eg, a follow-up visit may be labeled as
for immunizations, acne follow-up).
Alcohol Screening in Youth

Practitioners should strive to establish good rapport with adolescent patients and
encourage honest answers. Building in alone time (without parents) during the
visit and explaining confidentiality policies (see above) can facilitate it.
Explaining the purpose of asking about sensitive issues can further promote a
trusting relationship and alleviate the youth’s perception of being singled out
(“My goal is to help my patients to be healthy and that’s why I talk to all my
patients about alcohol use and other health risks”).
The NIAAA guide recommends using two screening questions about the
past year alcohol use to facilitate stratification of the child’s drinking behavior
into a lowest-, moderate-, or highest-risk category. The choice of initial
questions depends on the child’s school level and age (Table 22-3). For
elementary and middle school kids, the first screening question is about their
friends’ alcohol use (any use), and the second question is about the patient’s
personal alcohol use. For high school students, the first screening question is
about the patient’s personal alcohol use frequency in the past year, and the
second question asks about friends’ binge drinking. Presence of friends who
drink among younger kids or friends who binge drink among high school
students has been shown to increase the patient’s risk of unhealthy substance use
and should trigger additional probing questions.
TABLE 22-3 Two-Question Initial Screen: Ask About

Personal Alcohol Use and Friends’ Drinking
Assessment of Severity in Youth: At-Risk Drinking and

Youth who do not drink (negative screen) should be praised and counseled on
the continuation of their healthy behaviors. It is helpful to elicit and affirm their
reasons for not drinking and educate about risks associated with drinking. Jointly
with the clinician, they should also explore plans on how to continue staying
alcohol free when friends drink and be advised never to ride in a car with a
driver who used alcohol or drugs. Nondrinkers with nondrinking friends should
be rescreened at least yearly. However, those with drinking friends should be
rescreened more frequently, best during the next visit.
All drinking youth should be evaluated in more depth to assess and stratify
risk (Table 22-4). Any past year drinking places an elementary school student in
a high risk and a child 12-15 years old (middle or early high school) in a
moderate-risk category. Moderate- and highest-risk patients should be
additionally evaluated for the presence of AUDs. Additional questionnaires,
asking in more detail about alcohol consumption and related problems, can assist
this process.
TABLE 22-4 Adolescents Who Report Drinking in the

Past Year: Risk Stratification by Age and the Number of
Past Year Drinking Days
Elementary school: 9-11 years old; middle school: 11-14 years old; high school: 14-18 years old.
Substance Use Assessment Questionnaires for Youth

For drinking youth, several brief questionnaires to help assess in more depth and
gauge risk of the adolescent’s substance use are available. They can identify
consequences that can then be discussed during motivational interviewing (MI)
and intervention. Although the AUDIT can be used in drinking adolescents,
lower thresholds are used to identify unhealthy alcohol use than in adults (31).
The CRAFFT, on the other hand, is an easy-to-use, validated, and reliable six-
question survey, inquiring about both alcohol and drug use in several contexts
(Car, Relax, Alone, Forget, Friends, Trouble). It is endorsed by the NIDA and
the AAP and can discriminate between substance use, at-risk use, and disorder in
adolescents (33). It can be prefaced with the phrase “in the past year” and
administered in verbal, electronic, or paper–pencil format. Positive responses to
two or three of the CRAFFT questions raise suspicion for substance use
condition that warrants further inquiry, while four or more “yes” responses
suggest substance dependence (moderate to severe disorder).
Brief tools have also shown promise as initial screening tools for unhealthy
alcohol or cannabis use among young people (12-21 years old) in the emergency
department (ED) (34). Positive screen results identify youth at risk for having an
alcohol or cannabis use disorder who should receive a more detailed assessment,
most likely on an outpatient basis. A two-question instrument may provide a
“Quick Screen” in the ED to detect a probable AUD (“In the past year, have you
sometimes been under the influence of alcohol in situations where you could
have caused an accident or gotten hurt?” and “Have there often been times when
you had a lot more to drink than you intended to have?”) (studied among adults)
(35,36). Youth answering “yes” to one or both of these screening questions have
an eight times higher risk of having an AUD. Youth who report cannabis use
more than two times over the previous year on a one-question screen for
unhealthy cannabis use (Diagnostic Interview Schedule for Children, DISC)
(37,38) have an almost sevenfold risk of having a cannabis use disorder
compared to those who used cannabis less frequently (“In the past year, how
often have you used cannabis [0 to 1 time; >2 times]?”). In general, it is worth
noting that many available screening instruments aim at identifying substance
use disorder; for most (if not all) youth, any use, and especially at-risk use,
should be inquired about and approached seriously.
Just as with adults, it is important to clarify what a “single” drink means
while inquiring about alcohol quantity. Charts defining “standard” drink
equivalents are very useful. Incorporating “what else I know” about the patient
into the risk assessment and then intervention can strengthen and personalize
treatment; for example, family history of substance use disorders, permissive
environment at home toward substance use, or low parental involvement would
heighten concern about the degree of risk.
Alcohol Brief Intervention in Youth

All drinking youth should receive BI, with BI principles similar to those as for
adults. Lowest- and moderate-risk patients without an AUD should be advised to
stop (or at least reduce) drinking and receive counseling similar to that described
above for the nondrinking youth, though adjusted appropriately. Referral to
addiction treatment should always be considered for the highest-risk patients and
those with an AUD. In addition, adolescents who display “acute danger signs”
will need immediate intervention and, likely, parental or guardian involvement
that may require breaking of the minor’s confidentiality. The most common and
potentially lethal acute danger signs include driving under the influence of
alcohol or drugs; high-amount intake (eg, prior poisoning or overdose);
combining alcohol with drugs, especially sedatives; engaging in high-risk
behaviors in relation to substance use (eg, unprotected sex, injuries due to risks
taken); signs of AUD; or injection drug use (36,38).
Follow-up is crucial for the success of attaining treatment goals by both
adults and youth (38). Negotiating the timing of follow-up with the patient as
well as scheduling it for additional reasons (eg, acne) may increase the
likelihood that the patient keeps that appointment. As with adults, the starting
point of the follow-up evaluation is to ask the patient if he or she was able to
meet and sustain goals, prior to the reassessment and risk restratification.
Treatment goals and plans should be revised as appropriate and as based on the
newly obtained information and the patient’s preferences.
CURRENT EVIDENCE ON SCREENING

AND BRIEF INTERVENTION: A BRIEF
SUMMARY
Screening and Brief Intervention for

Unhealthy Alcohol Use
With the caveat that randomized controlled trials of SBI generally rely on
patients’ reports of drinking, which may be subject to bias (reporting what the
participant believes the interviewer, who has recommended less use, wants to
hear), a meta-analysis estimates a 10% absolute risk reduction in risky drinking
associated SBI for unhealthy alcohol use (39). Its health impact has been
compared to other cost-effective preventive services such as screening for
colorectal cancer, hypertension, visual acuity (for adults > 64 years of age) and
to immunization for influenza and pneumococcal infection. However, the impact
of SBI is less certain for individuals with existing AUD and referral rates are
generally low (40,41). Moreover, in contrast to other commonly performed
medical screening services, screening and counseling for unhealthy alcohol use
continues to be delivered at much lower rates.
A nationally representative Internet-based survey of over 2500 adult primary
care patients in 2013 showed that just under 1 in 4 patients received alcohol
screening in the past year, with men and women being screened at similar rates.
Individuals with less than a college degree, and non-Hispanic black patients,
were significantly less likely to be screened relative to college-educated non-
Hispanic white patients (42).
A number of barriers can impede SBI implementation in the clinical setting.
These include adequate resources and staff training, and the nonstigmatizing,
nonstereotyping identification of those at risk, critical to facilitating delivery of
SBI in primary care setting (43). The Committee on Trauma of the American
College of Surgeons has recommended that all level I and II trauma centers be
equipped with alcohol screening tools and that level I centers offer a brief
intervention when necessary (41,44). In trauma settings, SBI may reduce
drinking, drinking-related harms, and recurrence of injuries requiring ED care or
hospital admissions among people with injury and at-risk drinking (45–47).
However, the overall evidence is not as strong as for a primary care setting—a
recent meta-analysis on 28 separate randomized controlled trials of SBI in ED
settings including 14 456 patients revealed very small effect sizes on subsequent
drinking and ED visits (48).
Indeed, evidence from individual studies in the ED settings is mixed; some
suggest SBI can reduce drinking and result in fewer subsequent ED visits among
at-risk drinkers (48–50) while other high methodologic quality studies have
yielded null results (51–56).
In general inpatient medical settings, evidence on the effectiveness of
opportunistic alcohol SBI is inconclusive and suggests that SBI may be
beneficial (54,55,57) but does not work as well as in primary care patients. One
of the key issues in this setting is that the vast majority of general medical
inpatients, identified as “positive” by screening, have DSM-IV–defined alcohol
dependence (54).
Limited evidence suggests that SBI can reduce morbidity and mortality (56).
SBI appears to reduce drinking in adults including young adults ages 18-25 (23)
and older adults ages 65 and older (58,59), college students (60–62), pregnant
women, and women of childbearing age (63,64), though in the latter, the
evidence is not as strong. According to the USPSTF guidelines, there is still
insufficient evidence on alcohol SBI efficacy in adolescents; however, the
growing evidence is encouraging, and main professional organizations and
expert panels advise conducting SBI in youth at least annually, starting at age 9
years (13,29,31,32,65).
Although a single, short 5- to 15-minute intervention may be helpful, a
multiple-contact BI, usually including one to three booster sessions, have been
shown to reduce self-reported drinking and are recommended (66,67). The
optimal interval for SBI is unknown. Patients with past alcohol-related
consequences, young adults, and other high-risk groups (eg, smokers) may
benefit from frequent screening and, if indicated, BI (66). The counseling style
of effective BIs is based on MI and commonly includes elements such as
empathy, feedback, advice with an emphasis on patient responsibility and self-
efficacy, and a treatment plan with a menu of options. The BI studies with the
largest effect sizes utilized primary care clinicians to deliver the intervention
(67).
Electronic screening and brief intervention (e-SBI) approaches for alcohol
use have shown promise in a variety of contexts including trauma and other
medical settings (68–72), college students (73,74), at-risk users (75–79), and
pregnant and postpartum women (80–83). Technology may facilitate the process
of identifying and initially addressing alcohol (and drug) use due to the
perception of privacy by the user and nearly unlimited moment-to-moment
access, particularly as it pertains to smartphone-based tools (ie, apps). However,
effect sizes in systematic reviews of randomized trials have been very small.

Unhealthy Drug Use
Based on a limited but growing number of randomized trials now including
thousands of patients in several settings, the USPSTF maintains that current
evidence is insufficient to assess the balance of benefits and harms of screening
adolescents, adults, and pregnant women for illicit drug use (66). In recent years,
there are an increasing number of randomized controlled trials of SBI for
unhealthy drug use in primary care settings (75,84–87) and emergency
departments (88,89) parallel to growing national recognition of morbidity and
mortality associated with prescription drug misuse in the United States,
especially prescription opioid misuse (90–92), and increasing acceptability and
legalization of cannabis (93). Results on SBI for drug use to date have yet to
support widespread implementation (94). In fact, the bulk of evidence from
high-quality randomized trials suggests lack of efficacy, and NIDA and NIH
leaders have recommended scientists “go back to the drawing board” as a result
(95).
SBI for Prescription Opioid Misuse

In 2014, an estimated 10.3 million persons reported using prescription opioids
nonmedically (ie, using medications that were not prescribed for them or were
taken only for the experience or feeling that they caused) (91). Emergency
department visits involving misuse of prescription opioids increased 153%
between 2004 and 2011, and admissions to substance use disorder treatment
programs for prescription opioid use disorders more than quadrupled between
2002 and 2012 (96). Between 2000 and 2014, the rates of death from
prescription-opioid overdose nearly quadrupled (from 1.5 to 5.9 deaths per 100
000 persons) (90).
Even more alarming is the increasing availability of powerful illicitly
manufactured synthetic opioids, which may have emerged in response to
increasing illicit opioid demands. Between 2013 and 2014 alone, while the age-
adjusted rate of death involving methadone remained unchanged, the age-
adjusted rate of death involving natural and semisynthetic opioid pain relievers,
heroin, and synthetic opioids other than methadone (eg, fentanyl) increased 9%,
26%, and 80%, respectively. The sharp increase in deaths involving synthetic
opioids other than methadone in 2014 coincided with nationwide law
enforcement reports of increased availability of illicitly manufactured fentanyl, a
synthetic opioid with 100 times the potency of morphine, typically only used in
intraoperative settings in the context of close cardiopulmonary monitoring (97).
Research designed to develop screening methods for the detection of
prescription opioid use disorder has been growing in response to this epidemic.
Most studies have focused on survey-based screening for aberrant, drug-related
behaviors and toxicology screens. Four specific aberrant behaviors have been
strongly associated with DSM-IV–defined opioid dependence; these included
early refills, feeling intoxicated, self-increasing dose, and oversedating oneself
(98). One screening tool that is commonly used in the ambulatory care setting is
the Screener and Opioid Assessment for Patients with Pain-Revised (99). This
questionnaire was derived and validated in specialty pain clinic patients and is
widely used in both pain clinics and primary care practices. In addition to
screening instruments, 49 states have created Prescription Drug Monitoring
Programs (PDMPs). These tools, implemented on a state-by-state basis, are
online databases that list patients’ narcotic prescription histories, including the
number of prescribers and pharmacies utilized (100–102).
Unfortunately, no screening tool has been validated for universal screening
in primary care for prescription opioid misuse. There is also limited literature to
support the efficacy of SBI for prescription opioid misuse or disorder. Although
not considered traditional BI, patient–prescriber agreements for prescription
opioids often incorporate many of the basic BI principles including a patient-
centered agreement to minimize or stop alcohol and illicit drug use and obtaining
these medications from other physicians.
NIDA recommends the NIDA-Modified ASSIST questionnaire (described
above) for prescription drug misuse screening. The four-question–modified
CAGE survey (felt the need to cut down, annoyed when someone suggested to
cut down, felt guilty about use, and used first things in the morning to calm
down) can also be implemented, as described in the SAMHSA’s screening tools
(www.integration.samhsa.gov/images/res/CAGEAID.pdf); however, this latter
tool is not particularly useful for screening for the spectrum of current unhealthy
substance use or for opioid misuse. While there is limited information on the
sensitivity and specificity of routine toxicology drug screening in opioid-treated
chronic pain patients in primary care settings, this has become a routine practice
in many regions to detect substances not prescribed and confirm use of the
prescribed opioid. But this is not SBIRT—such testing is done to monitor the use
of prescription medications and to assess for illicit drug use in this subset of
patients at high risk.
Technology-Based Interventions for

Unhealthy Drug Use
There is now a substantial evidence base regarding the use of technology-based
(computerized, Internet-based, text-messaging, or smartphone) interventions in
addressing unhealthy alcohol use (69) and tobacco use (68). Abstinence from
tobacco use in college students has been shown to respond to stand-alone
computer programs (n = 10 studies), Internet (n = 5 studies), telephone (n = 3
studies), and mobile SMS (n = 2 studies) (103). However, research on
technology-based interventions that specifically target other drugs is
comparatively sparse. Of note, Internet interventions that target alcohol use have
not shown secondary (ie, spillover) effects on illicit drug use (104). Cannabis use
has been most frequently studied, and may respond to technology-based
approaches (105). According to a meta-analysis of 10 studies involving 4125
participants, frequency of cannabis use shows small statistically significant
reductions following Internet and/or computer-based intervention (106).
SYSTEMATIC REVIEWS AND META-

ANALYSES OF SCREENING AND BRIEF
INTERVENTIONS FOR UNHEALTHY
ALCOHOL USE
The following papers, among others, were used to support the summary
statements in the previous sections. What follows is a brief overview of SBI-
related research for unhealthy alcohol use and illicit drug use/disorders.
Tansil et al conducted a systematic review of the literature around the
effectiveness of e-SBI for alcohol (107). Although this review was published in
2016, it only included studies published up to October 2011 in the review. The
review included 31 randomized controlled trials in total, and was broken up by
studies that included all drinkers and those that included heavy drinkers only.
Most studies demonstrated a reduction in self-reported alcohol-related outcomes
following the intervention and changes were most consistent across studies in
the domains of frequency of heavy episodic (binge) drinking (median 16.5%
reduction) and amount of alcohol consumed (median 23.9% reduction).
A meta-analysis of randomized controlled trials, by Glass et al. in 2015,
provided an overall evaluation of the effects of brief alcohol interventions (40)
on referral to and attendance at treatment. The review analyzed nine studies with
over 900 participants who received an intervention. Interventions included in the
meta-analysis mainly included brief advice and motivational interviewing.
Postintervention rates of alcohol treatment were low across all studies and
intervention/control groups; the review found no effect of SBI on referral to
treatment.
A systematic review by Jonas et al. evaluated the benefits and harms of SBI
for unhealthy drinking among adolescents and adults. The 23 included trials
generally focused on “nondependent”(based on DSM IV) drinking, Jonas et al.
(39). The best evidence for efficacy was for brief (10 to 15 minute) multicontact
BIs. This review found a moderate strength of evidence supporting BI efficacy
for self-reported drinking reduction among adults with nondependent unhealthy
alcohol use as well as young adults or college students who engage in at-risk
drinking. Compared to controls, adults with unhealthy drinking reduced their
consumption by 3.6 drinks per week (10 trials, 4332 participants), with 12%
fewer adults reporting heavy drinking (7 trials, 2737 participants) and 11% more
adults reporting drinking below the recommended limit (9 trials, 5973
participants) over 12 months. Among young adults and college students, BI also
resulted in decreased alcohol use (1.7 fewer drinks per week; 3 trials, 1421
participants) and heavy drinking (0.9 fewer heavy drinking days per month; 3
trials, 1448 participants). The review did not find sufficient evidence to draw
conclusions about SBI efficacy for pregnant women, adolescents, and alcohol-
dependent adults, or for the reduction in injuries, accidents, or alcohol-related
liver problems among adult “unhealthy drinkers.” In general, little or no
evidence of SBI harms was found though consequences of confidentiality
breaches were not specifically studied.
Solberg et al. conducted a meta-analysis of primary care studies and
evaluated the clinically preventable burden (CPB) and cost-effectiveness of SBI
implementation and compared these values across other recommended
preventive services (108). The CPB was calculated as the product of
effectiveness times the alcohol-attributable fraction of both mortality and
morbidity (measured in quality-adjusted life years, or QALYs). Cost-
effectiveness from both the societal perspective and the health system
perspective was estimated. Randomized controlled trials (RCTs; n = 10) and
cost-effectiveness studies were included. The mean percentage of SBI
effectiveness for both heavy drinking and hazardous drinking in primary care
was found to be 17.4% (range, 9.8% to 30.1%), reflecting behavior change at 6
months to 2 years after intervention. The calculated CPB was 176 000 QALYs
saved over the lifetime of a birth cohort of 4 000 000 people. From both the
societal and health system perspectives, SBI is calculated to be cost effective and
may be cost saving, assuming that the self-report outcomes are accurate. This
meta-analysis suggests SBI as one of the highest-ranking preventive services
among the 25 effective services evaluated using standardized methods. As
current levels of delivery are the lowest of comparably ranked services, SBI
deserves special attention by clinicians and care delivery systems for
improvement.
A meta-analysis was conducted by the Cochrane Group, led by Kaner et al.,
to evaluate the effectiveness of SBI to reduce alcohol consumption among
nontreatment-seeking patients in primary care settings, including EDs (109). The
meta-analysis included 21 RCTs (n = 7286 participants), showing robust results
that participants receiving SBI significantly reduced their self-reported alcohol
consumption as compared to the control group (mean difference, −41 g/wk or 4-
5 units), with substantial heterogeneity noted between trials. The percentage of
heavy drinking and binge drinking adults was significantly reduced in the SBI as
compared to the control group. The analysis confirmed the benefit of SBI in men
(significant mean difference, −57 g/wk, ie, four self-reported standard drinks)
and women (nonsignificant mean difference, −10 g/wk was small). When
compared with brief BI, extended BI was associated with a greater reduction in
alcohol consumption (mean difference = −28 g/wk not statistically significant)
and an increased reduction in alcohol use of 1.1 g/wk and for each extra minute
of treatment exposure (p = 0.06). Reduction of drinking was also observed in
some control groups. Mean loss to follow-up was 27%, with more subjects lost
in the SBI than control groups (significant 3% difference). The results of this
meta-analysis are broadly similar to previous findings in primary care samples
and showed that SBI consistently produced modest reductions in self-reported
alcohol consumption. The effect was clear in men at 1 year of follow-up but
unproven in women. Of important note given self-reported outcomes, there was
no effect found of brief intervention on biologic measures reflecting alcohol
consumption.
The systematic review by Saitz evaluated efficacy of alcohol SBI in primary
care, with the main focus on effects for those with very heavy alcohol use or
DSM-IV–defined dependence. The review identified 16 RCTs (n = 6839
patients) (110). However, only two of these RCTs did not exclude patients based
on very heavy drinking or dependence. One of these studies, in which 35% of
175 Mexican American patients (mostly men) had dependence, found no
difference in drinks per week or severity scores between groups, and the other, in
which 58% of 24 women with dependence, showed no difference in alcohol
consumption between groups. Findings of this review highlight the absence of
evidence and the need for further research on SBI efficacy in primary care
patients with alcohol dependence or very heavy drinking.
A systematic review and meta-analysis by Beich et al. evaluated the
effectiveness of screening, as a part of an SBI program, for excessive alcohol use
in general practice. The eight included studies used health questionnaires for
screening, and the BIs included feedback, information, and advice.(76). Of 1000
screened patients, 90 screened positive and required further assessment, after
which 25 qualified for BI. After 1 year, 2.6 reported that they drank less than the
maximum recommended level. Although SBI can reduce self-reported excessive
drinking, screening in general practice may be inefficient as a precursor to BIs
targeting excessive alcohol use. This meta-analysis raised questions about the
feasibility of screening in general practice for excessive alcohol use.
A systematic review by the Cochrane Group, led by Dinh-Zarr, assessed the
effect of interventions intended to reduce alcohol consumption or prevent
injuries or their antecedents among “problem drinkers” in diverse settings (77).
Seventeen RCTs were included. Among those, seven evaluated BIs in the
clinical setting. BIs were associated with a significant reduction of injury-related
deaths (RR = 0.65) and showed beneficial effects on diverse nonfatal injury–
related outcomes. Interventions, including BIs, for problem drinking appear to
reduce injuries and their antecedents. One should use caution in applying these
results to SBI, however, since these were studies of BI, not universal screening
and SBI in primary care settings.
INDIVIDUAL STUDIES OF SCREENING

AND BRIEF INTERVENTION FOR
UNHEALTHY ALCOHOL USE
Primary Care Settings

SBI is efficacious for alcohol “misuse” (unhealthy alcohol that has not as yet
developed into a pathologic disorder) and recommended in primary care settings.
Implementation of SBI in primary care settings can allow for a better integration
of medical care and substance use disorder treatment. Such an integrated
approach may benefit individuals with substance use–related medical conditions
and be cost effective compared to a “treatment-as-usual model,” in which
primary care and substance use disorder treatment are provided separately (111).
Project TrEAT and Project Health are examples of the positive SBI trials in
primary care. Project TrEAT was the first US study to evaluate long-term
efficacy and cost–benefit of SBI among 774 at-risk drinkers in primary care (58).
After two short BI sessions delivered by a clinician, each followed by a phone
call, adults drinking at-risk amounts who received BI significantly decreased
alcohol use, health resource utilization, and alcohol-related costs compared to
controls. These effects were observed at 6 months and maintained during a 48-
month follow-up.
In Project Health, after a very short BI, delivered by a clinician as part of a
routine primary care visit, participants significantly reduced self-reported
drinking and were less likely to report return to at-risk drinking than controls at 6
and 12 months (112,113). Only one study evaluated efficacy of SBI over a
period >4 years (114). After up to three sessions of BI, delivered over a 6-month
period, 554 at-risk and harmful drinking adults in the BI group significantly
reduced their self-reported drinking at 9 months compared to “no-treatment”
controls. The differences between the groups dissipated at 10-year follow-up;
however, at 10 years, both the BI and control groups tended to drink less by self-
report than at baseline or at 9 months, which suggests “assessment effects” or a
favorable natural history of risky alcohol use.
Hilbink et al. conducted an RCT evaluating effects of a multifaceted
intervention in primary care aimed at the reduction of unhealthy drinking.
Physician practices in the Netherlands were randomized to control condition
(unhealthy drinkers were mailed the guidelines and information letters about
unhealthy drinking) or the “improvement intervention.” The intervention
included the entire clinical practice team who received short training in SBI, thus
facilitating changes on the organizational and staff awareness and skill level,
with emphasis on educating clinicians; unhealthy drinkers in these practices
received a personalized feedback letter with a suggestion to discuss drinking
further with their clinician. Among 6318 screened, 712 patients from 70
practices scored positive for unhealthy non-DSM-IV–defined alcohol-dependent
drinking (AUDIT score 8-19). Over the course of 2 years, a large proportion
(41.6%) of unhealthy drinkers reduced drinking to a low-risk level; however, a
significantly larger reduction was demonstrated in the control (47%) than in the
intervention (35.5%) group. Although certain patient characteristics were
associated with drinking reduction (eg, older age, female sex, attitudes toward
drinking), characteristics of the practices were not predictive of decreased
alcohol use. The authors drew conclusions that “the intervention has been
counterproductive” and hypothesized that these unexpected results or, rather,
lack of favorable results of the clinic-based intervention may be related to the
overall low level of engagement of the participating clinicians. At the very least,
this study raises the possibility that SBI done poorly could risk harm (115).
One study supports the low engagement of primary care clinicians by
examining the levels of documentation as a proxy for communication about
alcohol and drug screening results (116). Health educators in this study assessed
potential patients for unhealthy alcohol consumption prior to the patient seeing
their primary care physician. If warranted, health educators provided a brief
intervention to patients. Health educators then completed a “provider education
form” to convey these results, but nothing was entered into the patient’s
electronic medical records. Of the 495 patients screened, 97% had risky
substance use, and the remaining 3% dependence. When examining medical
records, only 58% of patients with identified substance use had documentation
that matched the type of substance and rate of use. All patients with dependent
alcohol use had appropriate documentation, but only 64% of those with risky
alcohol use did. In addition, documentation of the brief intervention only existed
for 25% of patients, although all patients were provided with some type of
intervention. These low numbers make it challenging for primary care
physicians to follow-up appropriately with their patients about their alcohol use.
The lack of documentation also exposes PCPs to the potential of mishandling of
risky situations that their patients may be experiencing. It is impossible to test
the efficacy of brief interventions in a naturalistic setting if clinicians are
unwilling to properly document their efforts.
The efficacy of SBI in dental clinics is receiving increasing attention (117).
Thirteen different clinical practices were randomized to either receive the
intervention or participate as controls. In total, 103 heavy drinkers were included
in the study and assessed over the phone prior to their dental visits. Those in the
intervention group received 3-5 minutes of intervention personalized to the
individual’s drinking patterns and delivered by a dental hygienist. Follow-up
assessments were conducted at 3 and 6 months. By 6 months, those receiving
interventions reported having decreased their drinking by an average of 8 drinks
a week, while those in the control group decreased their drinking by an average
of 4 drinks per week. Despite the power limitations, this study points to an
additional potential setting for intervention on risky alcohol use.
Adolescents and Young Adults

Research on SBI efficacy for adolescent unhealthy drinking is limited, but its
results are encouraging. Rates of adolescent alcohol use range from 5% among
general ED admissions to nearly 50% among trauma admissions, and alcohol use
by adolescents is associated with increases in severity of injury and cost of
medical treatment (93).
Most recently, a review article in 2013 (94) examined 15 randomized
controlled trials for SBI in adolescents. The minimum age for inclusion in the
studies examined was 14, and the maximum age was 17 years. As such, studies
focusing on college students were excluded. In terms of screening, one study
found that structured screenings produced higher rates of detection of risky
substance use than routine screening traditionally used by primary care
physicians. Other studies highlighted the need to consider all youths in settings
such as community outreach centers as at risk for unhealthy substance use.
Screening for adolescents must be changed based on the context of the
screening, and it is important to remember that adolescents may not always tell
the truth on self-report screening measures. In addition, research is limited on
confirmatory measures such as blood alcohol testing due to the limits on the
logistics of collecting data and extrapolating to long-term patterns of use. Brief
interventions for adolescents range from short conversations with a physician to
lengthier and repeated exposures in a school setting. Motivational interviewing
has repeatedly been found to be an effective tool for change for adolescents with
risky alcohol use. Despite this finding, overall effectiveness of brief
interventions for adolescents is limited by the small number of studies, and
heterogeneous nature of the participants and interventions used.
A 2012 published systematic review by Yuma-Guerrero et al. focused on the
efficacy of alcohol SBI in adolescents in acute care settings (31). The review
identified seven RCTs evaluating SBI effects on alcohol consumption and/or
consequences among 3309 risky drinkers, aged 12-24 years, all patients in the
EDs of the level I trauma centers. All but one study used motivational
interviewing (MI)-based interventions. These studies produced overall promising
but inconsistent results. The authors concluded that the evidence is not sufficient
at this point to provide an unambiguous support for the SBI efficacy for
adolescent ED patients who engage in risky drinking. The Yuma-Guerrero et
al.’s review included the following RCTs of the ED patients: Monti et al.
evaluated adolescents aged 18-19 years (n = 94) who either tested positive
(blood alcohol level) for or self-reported alcohol use. Although both the
intervention and control groups reduced their drinking at 3 and 6 months, no
significant differences between the groups were found in alcohol consumption.
Compared to controls, the intervention group was less likely to report negative
consequences of drinking at 6 months (p < 0.05) though. Johnston et al. (118)
examined effects of SBI among 12- to 20-year-old adolescents (n = 631)
receiving ED care for injury. At 3- and 6-month follow-up assessments, both the
intervention and the control groups reduced prevalence of risky behaviors, but
there were no significant differences between the groups on alcohol-related
outcomes (driving after drinking, riding with an impaired driver, or binge
drinking). Spirito et al. evaluated outcomes of a single BI session in the ED
setting among 13- to 17-year-old adolescents (n = 152) admitted for an alcohol-
related injury (119). Over 12 months, both intervention and control groups
significantly reduced number of drinks per occasion; the groups did not differ on
alcohol-related outcomes. However, the subgroup of adolescents with
“problematic” alcohol use (almost 50% of the sample) reported significantly
more reduced frequency of drinking and high-volume drinking if they received
intervention (p < 0.01), indicating that BIs had some efficacy at least on self-
reports, particularly for adolescents engaging in the riskiest drinking behavior.
Maio et al. compared effects of an interactive computer program–based
intervention versus standard of care among 14- to 18-year-old ED patients (n =
655). There were no statistically significant differences between the groups on
main outcomes. Both groups showed a reduction in unhealthy alcohol use and
“binge” drinking at 3 months, but these levels returned to baseline at 12 months.
Interestingly, within the subgroups of adolescents, who reported either riding
with an intoxicated driver or “drinking and driving” at baseline, those in the
intervention group showed greater improvement in unhealthy alcohol use
compared to controls (120).
A meta-analytic review by Jensen et al. assessed effectiveness of MI-based
BI for adolescent substance use (36). Among 21 identified controlled trials of
BIs, including 5471 adolescents aged 12-23 years recruited primarily from the
community settings, most addressed alcohol (n = 12) and marijuana (n = 12),
then multiple restricted substances (n = 9), tobacco (n = 7), and various street
drugs (n = 6). Meta-analysis revealed statistically homogeneous sample of effect
sizes, with an overall small but significant mean posttreatment effect size of the
MI interventions on self-reported outcomes that was retained over time. The MI
interventions appeared effective across a variety of self-reported substance use
behaviors, varying BI session lengths, and different settings, thus providing a
strong support for the effectiveness of MI interventions for adolescent self-report
of substance use behavior change.
A review by Tevyaw and Monti presented the use and efficacy of
motivational enhancement and other brief interventions for substance use,
particularly drinking, in adolescents and young adults (65). This review found
that positive results demonstrated in clinical trials using motivational
enhancement interventions with adolescents and college students primarily stem
from reductions in alcohol-related problems and, to a lesser extent, from
reductions in drinking. Although most young people do mature out of hazardous
drinking patterns, motivational enhancement–based interventions may help
accelerate that maturation process in high-risk individuals. The review
concluded that motivational enhancement–based BIs can decrease alcohol-
related negative consequences, reduce alcohol use, and increase treatment
engagement among adolescents and young adults. Grossberg et al. examined 226
primary care patients aged 18-30 years with at-risk drinking (23). Young adults
who received the BI significantly reduced self-reported drinking, had fewer ED
visits, motor vehicle crashes and events, and fewer arrests for controlled
substance or liquor violations over the 4-year follow-up (61). SBIs seem feasible
and accepted by young adults (121).
Older Adults
SBIs seem to be effective for older adults (58). Project GOAL, conducted in
parallel to Project TrEAT and based on similar methodology, showed that SBI
can decrease self-reported alcohol use among older primary care at-risk drinkers
during the 2-year follow-up (122).
College Students
About 40% of college students report binge drinking in the prior 2 weeks and a
third meet criteria for DSM-IV–defined alcohol abuse and 6% for alcohol
dependence in the prior year (34). SBIs seem effective for reducing at-risk
drinking in college students in general (60), in mandated college students (123),
and in students admitted to the ED (124–126). College students seem receptive
to alcohol SBIs (60,61).
While there are a limited number of SBI studies conducted in healthcare
settings, there is a very robust set of studies testing counselor-delivered brief
intervention outside of such settings. The best known of these studies were
conducted by Marlatt et al. and Baer et al. This study included 461 college
freshmen, identified as at-risk drinkers or a “normative control” group during
their final high school year. At-risk drinking students were randomized into the
“no-treatment” control arm or the BI arm, which received one to two BI
sessions, delivered by psychologists, with a personalized feedback letter. Over 4
years, at-risk students, in both intervention and control groups, reported
significantly reduced drinking and related harmful consequences, with changes
significantly favoring the BI group. These long-term benefits occurred even in
the context of maturational, natural trends, observed in the “normative control”
group (61).
A review of counselor-delivered BI that was conducted by Larimer et al.
summarized the results of 16 studies evaluating effects of alcohol SBIs in
college settings and concluded that research provides strong support for the
efficacy of SBIs (62). The strongest evidence exists for interventions in the form
of brief, personalized, individual, motivational feedback-based interviews. There
also is emerging support for the efficacy of mailed or computerized feedback
alone in producing at least short-term reductions in students’ reported alcohol
consumption. A systematic review by Zisserson et al. reviewed evidence for the
utility of SBIs delivered without direct, real-time contact to college students
engaging in at-risk drinking (127). The results suggest that “no-contact”
interventions (eg, printed materials or computer-based modalities) are feasible
and may have efficacy in this population. The “no-contact” interventions may be
helpful with broader dissemination of SBIs to college students.
A more recent meta-analysis of SBI among college students was conducted
by Fachini et al. They reviewed 18 clinical trials that varied in sample sizes from
54 to 1275 students and found modest reduction in self-reported alcohol use and
harms over a 12-month period (124).
In addition to the traditional counselor-delivered brief intervention, there is
an emerging literature with BI being conducted by primary care clinicians in
student health centers. Fleming et al., in an RCT, conducted across five student
health centers in the United States and Canada, randomly assigned 986 subjects
to usual care or brief intervention, and delivered by 15 physicians and 3 nurse
practitioners. They found significant modest reductions in self-reported alcohol
use and harm in the experimental group compared to the control group (p < 0.05)
(128). Schaus and colleagues also reported positive findings from their study of
BI delivered by physicians in the context of routine care in a student health clinic
(129).
INDIVIDUAL STUDIES OF SCREENING

AND BRIEF INTERVENTION FOR
UNHEALTHY DRUG USE
Evidence on SBI efficacy for illicit drug use or disorders is limited and
inconsistent (88), potentially reflecting heterogeneity in the population of
individuals who engage in risky drug use, and persistence of a behavior that is
not socially sanctioned. Computerized interventions might be more effective
with regard to the use of some substances more than others (130). Pregnant and
postpartum women have reported high acceptability of computer-based BIs
(80–83). However, the studies on behavioral and substance use outcomes
following intervention have yet to support its efficacy and provide substantial
evidence of lack of efficacy (86,87,89,131).
Studies Suggesting Benefit of BI for Drug Use

Some promising effects of SBI on substance use have been reported in adults
reporting cocaine and heroin use identified by screening though effect sizes were
small. Bernstein et al. examined the efficacy of a single BI session, delivered by
a “peer educator” and augmented by a follow-up phone call, compared to a
handout-only control condition (132). Among 1175 adult cocaine and/or heroin
users, recruited from urgent care and other outpatient settings (23 660 were
screened using the Drug Abuse Screening Test), at 6 months, those in the BI
group were 5% more likely to be abstinent from cocaine (22% vs. 17%) and 9%
more likely to be abstinent from heroin (40% vs. 31%) and report greater
improvements on the drug and medical subscales than controls who received
written advice and a list of referral options. This study was particularly
important because it reported biologic outcomes (drug testing of hair).
Gelberg and colleagues found a reduction in reported days using individuals’
self-identified highest scoring drug (HSD) 3 months following BI relative to
usual care (84). Participants in this study were 334 adult primary care patients
(171 intervention; 163 control) with risky psychoactive drug use scores of 4-26
on the World Health Organization (WHO) Alcohol, Smoking, and Substance
Involvement Screening Test (ASSIST). The interventions consisted of 3-4
minutes of clinician advice to quit/reduce their drug use reinforced by a video
doctor message, a health education booklet, and up to two 20-30-minute follow-
up telephone drug use coaching sessions. Intervention patients self-reported
using their HSD on 3.5 fewer days in the previous month relative to controls.
Moreover, no compensatory increases in use of other measured substances were
found. The results may not be valid as they were not confirmed by biologic
testing, and surprisingly, the effects seemed to be limited to a more severe (more
frequent using) subgroup; however, if valid, they might be explained by having
the intervention done by the patient’s own clinician, a video doctor, and a
lengthy follow-up contact, the latter two of which are more than usually occurs
in most SBI approaches.
Gryczynski and colleagues randomized 360 adult community health center
patients with moderate-level drug misuse to a computerized brief intervention
(CBI) versus an in-person brief intervention (IBI) delivered by behavioral health
counselors. Of note, this study included no inactive control group. Participants
were assessed at 0, 3, 6, and 12 months following the intervention using the
Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) and
laboratory analysis of hair samples. While there were no significant differences
in drug-positive hair tests over time or by condition, global ASSIST scores
decreased in both intervention conditions. This is a remarkably informative
observation since it implies that self-reporting social desirability bias could be a
major explanation for the results of all alcohol and other drug SBI studies that
find positive effects on self-reported use (if biologic measures of use do not
change). Furthermore, some differences in computerized versus in-person
modality were found regarding specific substances. CBI produced greater
reductions in substance-specific ASSIST scores for marijuana, alcohol, and
cocaine relative to IBI at 3 months; however, these initial differences dissipated
over time (85).
Studies Suggesting No Benefit of BI for

Unhealthy Drug Use versus Treatment as
Usual
Humeniuk et al.’s multinational study evaluated SBI’s efficacy for illicit drug
use (cannabis, cocaine, amphetamine-type stimulants, and opioids) among 731
primary care patients, aged 16-62 years, in four countries: Australia, Brazil,
India, and the United States. Screening was conducted using the ASSIST
questionnaire (133). Enrolled participants were randomly assigned to receive
usual care or a motivational BI that took, on average, 13.8 minutes and targeted
the drug receiving the highest ASSIST score. “Pooled” analyses showed that, at
3 months, those who received BI reported a reduction in total illicit substance
involvement scores compared to controls; however, the differences were very
small. Country-specific analyses indicated that profile of substance use changes
varied by country. Compared to controls, the BI group reported improved (a)
total substance use–related scores in Australia, Brazil, and India; (b) cannabis
scores in Brazil and India; (c) stimulant scores in Brazil and Australia; and (d)
opioid scores in India; in the United States, BI did not show efficacy for any
substance.
Saitz and colleagues conducted a 3-group randomized trial in 528 adult
primary care patients with drug use (Alcohol, Smoking, and Substance
Involvement Screening Test [ASSIST] substance-specific scores of ≥4) to test
the efficacy of two brief counseling interventions for unhealthy drug use (any
illicit drug use or prescription drug misuse)—a brief negotiated interview (BNI)
and an adaptation of motivational interviewing (MOTIV)—compared with no
brief intervention (87). The BNI is a 10- to 15-minute structured interview
conducted by health educators; the MOTIV is a 30- to 45-minute intervention
based on motivational interviewing with a 20- to 30-minute booster conducted
by master’s level counselors. Primary outcome was number of days of use in the
past 30 days of the self-identified main drug as determined by a validated
calendar method at 6 months. Secondary outcomes included other self-reported
measures of drug use, drug use according to hair testing, ASSIST scores
(severity), drug use consequences, unsafe sex, mutual help meeting attendance,
and healthcare utilization. At baseline, 63% of participants reported that their
main drug was marijuana, 19% cocaine, and 17% opioids. Mean adjusted
number of days using the main drug at 6 months was 12 for no brief intervention
versus 11 for the BNI group (incidence rate ratio [IRR], 0.97; 95% CI, 0.77-
1.22), and 12 for the MOTIV group (IRR, 1.05; 95% CI, 0.84-1.32; p = 0.81 for
both comparisons vs no brief intervention). There were also no significant
effects of BNI or MOTIV on any other outcome or in analyses stratified by main
drug or drug use severity.
Similarly, Roy-Byrne et al. demonstrated that brief intervention in the
primary care setting did not improve drug use outcomes compared with
enhanced care as usual in their randomized trial with blinded assessments at 0, 3,
6, 9, and 12 months in seven safety-net primary care clinics (134). Participants
received a single brief intervention using motivational interviewing, a handout
and list of substance abuse resources, and an attempted 10-minute telephone
booster within 2 weeks (n = 435); or enhanced care as usual, which included a
handout and list of substance abuse resources (n = 433). During the 12 months
following intervention, no significant treatment differences were found for self-
reported days of problem drug use, Addiction Severity Index–Lite (ASI) Drug
Use composite score, emergency department and inpatient hospital admissions,
arrests, mortality, or human immunodeficiency virus risk behavior. Of note, both
of these primary care studies had high follow-up rates, were large samples, and
confirmed self-report results with biologic outcomes.
Woodruff and colleagues’ randomized trial in 700 emergency room patients
also did not find a significant change in self-reported past 30-day abstinence at 6
months following a BI for illicit drug use relative to an attention-placebo
intervention (86). Similarly, a multisite randomized trial of 1285 emergency
room patients randomized to brief intervention with telephone boosters (BI-B);
screening, assessment, and referral to treatment (SAR); and minimal screening
only (MSO) found no significant differences at 3, 6, and 12 months in self-
reported days using the patient-defined primary problem drug, days using any
drug, days of heavy drinking, and drug use based on analysis of hair samples
(89). In sum, the largest and highest quality (follow-up, biologic outcomes) SBI
drug studies fairly conclusively find no efficacy for drug SBI.
SUMMARY
As commonly observed in medicine, the implementation and dissemination of
novel clinical approaches rarely follows the pace of scientific advances (135).
Alcohol SBI in primary care settings shows efficacy for reducing self-reported
use for people who drink risky amounts but do not have a disorder, findings
consistent across decades of research. The challenge remains to confirm that it
can affect any meaningful health outcomes consistently and retain efficacy in
real clinical practice. In general, this evidence has led to clear preventive
recommendations because SBI is thought to have minimal harm and cost,
patients should be informed about risky drinking regardless, and if the self-report
findings translate to effects on significant consequences as some studies suggest,
it could be very effective on a public health basis. Tobacco SBI is effective and
has been implemented widely. Drug SBI continues to be of questionable
efficacy; the same may be true for alcohol SBI in emergency, hospital, and
trauma settings. It is also worth noting that there are other reasons besides
screening, to advise patients with the goal of reducing harms and to identify and
address substance use. For example, in order to diagnose any symptom (eg, sleep
problem, high blood pressure, heartburn) or prescribe any medication
(particularly addictive pain medications), clinicians need to know if their
patients are using substances.
The evidence for the use of SBI for adolescents in general clinical settings
has strengthened over time, and currently, the major professional organizations
recommend the SBI services for youth, starting as early as age 9 years old.
Identification and treatment of illicit drug use and prescription drug misuse in
primary care and specialized clinical nonaddiction settings is a relatively new
area of work. Although evidence behind the utility of SBI for these risks and
conditions is not as strong as for alcohol or tobacco, the growing problem of
unhealthy drug use, especially misuse of prescription drugs, has led to the
endorsement of SBI for drugs by multiple professional organizations. More
research is needed on the use of SBI for hospitalized patients, a large proportion
of whom has DSM-IV–defined alcohol dependence, and on the impact of SBI on
morbidity and mortality. The use of SBI in psychiatric or co-occurring/dual
diagnosis settings remains an understudied area.
Since SBI is not simple or cheap to implement system wide, it is critical to
base practice on high-quality evidence. The study of SBI in all clinical settings
has become a high priority for federal funding initiatives. From clinical,
evidence, and research perspectives, much work needs to be done.
Implementation science, especially for substance use disorder–related treatment,
remains in its infancy with a rather limited number of scientists working in this
area. Electronic medical record systems offer an excellent opportunity to move
SBI into point of care and routine clinical practice. Even with the foregoing
areas that need further study, SBI has come a long way since the first large study
reported by Wallace et al. in 1988 demonstrated evidence for alcohol SBI
efficacy in primary care settings (136).

Pregnant Women
Nicolas Bertholet and Richard Saitz
Alcohol
Introduction
Alcohol has a harmful effect on the fetus that is completely preventable (by not
drinking) and can be responsible for lifelong consequences such as the fetal
alcohol syndrome (FAS; see Chapter 90, “Alcohol and Other Drug Use During
Pregnancy: Management of the Mother and Child”) (1–3). Alcohol is
teratogenic and, because of the absence of a developed blood filtration system,
the fetus is unprotected from alcohol. In addition to FAS, the consumption of 7
to 14 standard drinks per week is associated with developmental problems such
as moderate intellectual and behavioral deficits. These “fetal alcohol effects”
are similar to FAS but less severe and much more common (4–6). Alcohol
exposure during the first trimester of pregnancy is associated with low birth
weight, decreased birth length and head circumference, minor physical
abnormalities, and alcohol-related neurodevelopmental disorders (7). Second-
and third-trimester exposure can lead to developmental delay (4). Though
minimal alcohol consumption (eg, one drink every 10 days or less) might be
very low risk during pregnancy, no definitive threshold level of safe alcohol
consumption has been identified, mostly because of differences in fetal
vulnerability to the toxic effects of alcohol (8). Research suggests a linear
association between prenatal alcohol exposure and birth defects and growth
deficiencies, without evidence of a threshold (9–13). Effective prevention of
alcohol use by pregnant women is an important public health measure with
direct impact on infant outcomes.
Screening
The goal of screening is to identify pregnant women and women who are
considering or planning pregnancy and are using any alcohol and to advise
them to abstain (and to advise those who are abstinent to remain so). In the
early stages of pregnancy, before pregnancy recognition, alcohol consumption
is commonly reported (14). In addition, alcohol use and specifically heavy
drinking episodes are associated with sexual risk taking and unintended
pregnancies (15). The evaluation of prenatal alcohol use is challenging: many
women will reduce their alcohol use as soon as they are aware of their
pregnancy (16). Assessing alcohol use during the pregnancy will therefore not
be an accurate evaluation of what the alcohol consumption was at the time of
conception. Day et al. (17) have demonstrated that asking women about their
alcohol consumption before pregnancy was a more accurate measure of
drinking during the first trimester. Nevertheless, even though many women will
stop drinking during pregnancy, a significant proportion will continue to drink
(from low amounts to recurrent heavy drinking episodes) (14).
Because of fear and stigma associated with alcohol use during pregnancy,
pregnant women may underreport their alcohol consumption (18). In addition,
despite the widespread effort to inform women about the harmful effects of
alcohol use on the fetus (eg, via warning labels on containers), many women
believe that the consumption of small amounts will not have harmful
consequences. Studies failing to find effects of alcohol on the fetus and child
can erroneously prop up these beliefs when more accurate reporting would
clarify that failure to detect an effect is not the same as safe, or no effect, in
fact. Furthermore, individual studies often examine one outcome domain and
could only be reassuring in that regard and not for all possible alcohol harms
(19).
Screening instruments developed for general populations may perform less
well in women and in women of childbearing age (8). Consequently,
instruments have been developed specifically to ascertain drinking among
pregnant women. The T-ACE, based on the “CAGE” (20) (each letter stands for
one key word in each of the items), is a four-question instrument (21). T-ACE
stands for T (tolerance): How many drinks does it take to make you feel high?
A: Have people annoyed you by criticizing your drinking? C: Have you ever
felt you ought to cut down on your drinking? E (eye-opener): Have you ever
had a drink first thing in the morning to steady your nerves or get rid of a
hangover? Affirmative answers to questions A, C, or E are 1 point each.
Reporting tolerance to more than two drinks (T question) is scored 2 points. A
score of 2 or more is considered positive. The TWEAK, also derived from the
CAGE, is a five-question instrument (22). TWEAK stands for T (tolerance):
How many drinks can you hold? (positive if ≥6 drinks) Or How many drinks
does it take before you begin to feel the first effects of alcohol? (positive if ≥3
drinks) W: Have close friends or relatives worried or complained about your
drinking in the past year? E (eye-opener): Do you sometimes take a drink in the
morning when you first get up? A (amnesia): Has a friend or a family member
ever told you about things you said or did while you were drinking that you
could not remember? K: Do you sometimes feel the need to cut down on your
drinking? Affirmative answers to question E, A, K are 1 point each.
Affirmative answers to question W and T are 2 points each. The cutoff score is
2. The NET is a three-question instrument. It shares two questions with the T-
ACE (eye-opener and tolerance) and one with the Michigan Alcohol Screening
Test (MAST) (Do you feel you are a normal drinker?). The tolerance question
scores 2 points, the two other questions score 1 point each, and ≥2 is considered
positive.
Tested in routine assessment in gynecology and obstetrics services, the T-
ACE questionnaire showed better sensitivity compared to the Alcohol Use
Disorders Identification Test (AUDIT) and the Short MAST (SMAST) for a
lifetime diagnosis of an alcohol use disorder, risky drinking, and current
alcohol use in pregnant women (21,23). It outperformed obstetrics staff
assessment of any alcohol use (23), and its brevity makes it useful for routine
practice (24). Russell et al. (25) demonstrated that the TWEAK and the T-ACE
were sensitive for periconceptional risky drinking and outperformed the CAGE
and the MAST. At a cutoff of 2, the NET appears to be less sensitive than the T-
ACE, the TWEAK, and the MAST (22). In conclusion, the T-ACE and the
TWEAK are two brief questionnaires with satisfactory performance among
pregnant women (and those in the periconception stage). These two
questionnaires have similar sensitivities (69% to 88% for the T-ACE, 71% to
91% for the TWEAK) and specificities (71% to 89%; 73% to 83%) (26).
Although not specifically developed to screen pregnant women, the Alcohol
Use Disorders Identification Test—Consumption (AUDIT-C) (27), with a
cutoff ≥3, could also be used to screen for at-risk drinking (sensitivity: 95%;
specificity: 85%) and alcohol use disorders (sensitivity: 96%; specificity: 71%)
(26). The National Institute on Alcohol Abuse and Alcoholism (NIAAA) single
screening question has not been tested specifically among pregnant women.
According to a recent systematic review conducted on the performances of
seven instruments (T-ACE, TWEAK, CAGE, NET, AUDIT, AUDIT-C, and
SMAST), the three instruments with the best performances in pregnant women
receiving prenatal care are the T-ACE, the TWEAK, and the AUDIT-C (26).
Universal screening is currently recommended by numerous professional
organizations including the American College of Obstetricians and
Gynecologists, the American Academy of Pediatrics, the American Medical
Association, and the CDC (28).
Brief Intervention
Various studies of brief intervention included but did not specifically report on
women of childbearing age. One of the largest studies conducted in primary
care, a randomized controlled trial (Trial for Early Alcohol Treatment, project
TrEAT) (29), reported results of a subgroup analysis of 205 women aged 18 to
40. Brief intervention decreased the self-reported number of drinks consumed
in the past 7 days and the number of heavy drinking episodes in the past month
by about 20% to 25% (30). This study included women who drank more than
11 drinks per week, more than four standard drinks per occasion, or had
positive CAGE screening tests (2+) but excluded women with alcohol
dependence. The brief intervention consisted of two 15-minute visits with a
physician, 1 month apart, and supportive phone calls by a nurse 2 weeks after
each clinician visit. These results support the hypothesis that brief interventions
conducted in primary care among women of childbearing age with unhealthy
alcohol use are effective in reducing alcohol consumption and heavy drinking
episodes.
Recent systematic reviews focusing on efficacy of screening and brief
interventions for pregnant women conclude that brief interventions may result
in increased abstinence from alcohol, but evidence is scarce. A 2009 Cochrane
review identified four randomized controlled trials (not including trials of
pregnant women participating in treatment programs for alcohol dependence)
(31). These included a total of 715 pregnant women. Chang et al. (32)
randomly assigned 250 pregnant women identified using the T-ACE
questionnaire (score ≥ 2) as they attended prenatal care. Women with
gestational age >28 weeks and women without alcohol consumption in the 6
months preceding study participation were excluded. Women were randomly
assigned to a comprehensive assessment only or to a comprehensive assessment
and a 45-minute brief intervention. Brief intervention included review of the
subject’s health and pregnancy, review of lifestyle changes made since
pregnancy, articulation of drinking goals while pregnant and reasons for these
goals, recommendation of abstinence as the most prudent drinking goal, and
identification of high-risk situations for drinking and alternatives to drinking.
There was a similar decrease in alcohol consumption during pregnancy in the
control and intervention groups (0.4 vs. 0.3 drinks per drinking day,
respectively). The groups did not differ on the number of drinking episodes
either (1.0 vs. 0.7 episodes, respectively). There was an effect of brief
intervention on the subgroup of women (n = 142) who were abstinent at study
entry, with significantly more maintenance of abstinence in the intervention
group (86% vs. control group 72%), relative risk (RR) = 1.20 (95% confidence
interval [CI], 1.01–1.42). Unpublished data from Chang et al. (32) are reported
in the Cochrane review, showing no difference on abstinence from alcohol
between the intervention and the control groups (69% and 62% abstinence,
respectively). Two studies reported positive significant intervention effects on
abstinence: (33,34). O’Connor and Whaley (34) compared brief intervention
versus advice to stop drinking only, among 345 pregnant currently drinking
women. Brief interventions were delivered by trained nutritionists as part of an
individual nutrition education program and included education, feedback, goal
setting, cognitive-behavioral procedures, and a contract. There was a
substantial decrease in alcohol use in both groups, and authors reported a
significant effect of the intervention on abstinence by the third trimester:
Women in the intervention group were five times more likely to abstain than
were women in the control group (OR = 5.39, 95% CI, 1.59–18.25). Brief
intervention also improved birth weight and reduced fetal death (from 2.9% to
0.9%), though it is unclear that brief intervention impact on abstinence could
have plausibly accounted for effects of this size on these secondary outcomes.
Handmaker et al. (33) compared a 1-hour motivational interviewing
intervention to a written letter in a pilot study with 42 pregnant women. Results
showed no impact of the intervention except on a subgroup of women with the
highest drinking levels at study enrollment.
The fourth identified study, by Reynolds et al., compared a cognitive-
behavioral self-help intervention (including a 10-minute educational session
with a self-help manual to be completed over 9 days) to usual care. The study
recruited low-income pregnant women attending public health clinics in an
urban setting. Results suggest an intervention effect on abstinence, although the
difference between groups was not significant (RR = 1.25, 95% CI, 0.97–1.61).
There were no difference between groups on number of drinks per week (mean
difference −0.78 [−1.58; 0.02]) (35).
Gilinsky et al. (36) identified randomized and nonrandomized trials. Two
additional randomized trials not included in the Cochrane review were
identified (37,38). Reading at al. compared real-time ultrasound with verbal
and visual feedback to ultrasound without feedback and showed no difference
between groups (38). Chang et al. (37) compared a 25-minute brief intervention
that could involve a partner among pregnant women. The partner could be a
spouse, father of the child, or any other supportive adult and was chosen by the
pregnant woman. Women were enrolled as they initiated prenatal care in
obstetric practices and included if they scored 2 or more on the T-ACE,
reported any alcohol consumption while pregnant, reported consumption of at
least one drink per day in the 6 months before study enrollment, or drank
during a previous pregnancy. Women were excluded if they were receiving
treatment for a substance use disorder, had physical dependence to alcohol
requiring medically supervised withdrawal management, or used cocaine,
opiates, or other illicit drugs. The brief intervention included knowledge
assessment with feedback on drinking and pregnancy, goal setting, and
behavioral modification (identification of high-risk situations, alternative
behaviors, support from the partner). Both intervention and control groups
showed similar reductions in alcohol consumption. Brief intervention was,
however, effective in reducing drinking in a subgroup of women drinking more
heavily. In another subgroup analysis, authors reported a significant impact of
brief intervention when a partner participated.
Thus, research findings regarding the efficacy of alcohol screening and
brief intervention in pregnancy are largely null with perhaps one exception
(34), and some hypothesis generating subgroup analyses have suggested
avenues for further research and confirmation. Furthermore, it should be noted
that the Cochrane review concludes that the complexity of interventions limits
the determination of which type of intervention would be most effective and
that there is a lack of information on possible intervention effects on the health
of the babies (31).
Another study, not included in the Cochrane review, brings some
information: 300 women drinking more than three drinks per week during
conception were randomly assigned postpartum to receive or not receive a brief
intervention aimed at reducing prenatal alcohol use during the next pregnancy.
The intervention decreased alcohol use and improved infant outcomes (low
birth weight, fewer premature deliveries) (39).
Similar to the development of information technology–based brief
interventions for other populations, the use of electronic interventions is
developing for pregnant women and appears acceptable (40). A pilot study
tested the acceptability and efficacy of an electronic intervention (20-minute
electronic interactive session compared to a 20-minute intervention on infant
nutrition). Participants had to screen positive on the T-ACE and report drinking
weekly or more in the past month or having at least four drinks at least monthly
in the 12 months before becoming pregnant. Participants were recruited among
pregnant women seeking services at prenatal care clinics in Detroit. The
intervention was favorably rated by users (n = 48). The study showed medium-
size, but not significant, intervention effects on 90-day period prevalence (odds
ratio [OR] = 3.4, p = 0.19), and on a combined pregnancy outcome variable
(live birth, normal birth weight, no neonatal intensive care) (OR = 3.3, p =
0.09). (41).
Another intervention strategy consists of targeting the risk of alcohol-
exposed pregnancy by reducing drinking and/or increasing contraception when
alcohol use may occur. Floyd et al. randomly assigned 830 nonpregnant women
aged 18 to 44 years and currently at risk for alcohol-exposed pregnancies
(drinking more than five drinks any day or more than eight drinks per week and
having unprotected sex) to receive information or information and a brief
motivational alcohol intervention (four sessions) and one contraception
consultation (42). For up to 9 months, women in the intervention group were
significantly less likely to be at risk for an alcohol-exposed pregnancy (either
by drinking risky amounts or by not using effective contraception), confirming
results from a previous report (43). The same approach has been shown
successful among college heavy drinkers: Ceperich and Ingersoll published the
results of a randomized trial comparing motivational interviewing (lasting 60 to
75 minutes) and a feedback intervention to a minimal control condition
consisting of a brochure on women’s health (44). Female students at risk for
alcohol-exposed pregnancy aged 18 to 24 (n = 280) enrolled in the trial
(women were considered at-risk if they had sexual intercourse with a man in
the past 90 days, used contraception ineffectively, and consumed more than
four standard drinks per occasion at least once in the past 90 days or consumed
more than seven drinks per week on average). At 4-month follow-up, alcohol-
exposed pregnancy risk was lower in the intervention group (20%) compared to
the control group (35%). Control group assignment was associated with a
doubling of the risk (OR = 2.2). Considering that around half of pregnancies
can be unintended (45), and that alcohol use is associated with sexual risk
taking (15), this double approach is promising in reducing the risk of alcohol-
exposed pregnancies. A methodologic concern that applies to all of these
studies is that outcomes rely on unbiased self-report—which may not be
possible from women who advised to avoid alcohol use during pregnancy.
In 2010, Carson et al. (46) published consensus guidelines on alcohol use
and pregnancy. Although the efficacy literature is not robust, based on some
data and the precautionary principle, they recommend universal screening for
all pregnant women and women of childbearing age, emphasizing that
1. At-risk drinking should be identified before pregnancy to allow for

behavior change.
2. Healthcare providers should create a safe environment for women to report
alcohol consumption.
3. The public should be informed that alcohol screening and support for
women at risk is part of usual care.
4. Brief interventions are effective and should be delivered by healthcare
providers for women with at-risk drinking.
5. Healthcare providers should be aware of the risk factors associated with
women at-risk drinking.
6. Harm reduction and treatment strategies should be encouraged for women
continuing to use alcohol during pregnancy.
7. Pregnant women should be given priority access to withdrawal
management and treatment.
8. Providers should advise women that low-level consumption of alcohol in
early pregnancy is not an indication for termination of pregnancy.
In 2016, Wright at al. reported on conclusions from a 2012 expert meeting on

perinatal illicit drug use. Recommendations are to screen universally for at-risk
drinking, at the first prenatal visit and repeated at least every trimester for those
who screened positive, to provide brief advice to women who report cessation
of drinking and to provide brief intervention to women screening positive, and
referral to treatment for women in high-risk categories (28).
The U.S. Surgeon General states that no level of alcohol consumption by
pregnant women can be considered safe and that pregnant women and women
who may be or are considering pregnancy should abstain from alcohol. The
Center for Disease Control and Prevention also recommends that women who
are pregnant or might be pregnant not drink alcohol at all
(http://www.cdc.gov/vitalsigns/fasd/ accessed November 2016). Although it is
possible that very low amounts may not have adverse fetal effects in some
subgroups of pregnant women, the linear dose response, the potentially
irreversible and catastrophic effects, the limits of the ability of research to
prove the null, and the absence of a need to drink alcohol during pregnancy
support these recommendations.
Other Drugs
Introduction
Drug use is associated with medical complications in pregnant women (eg,
placental abruption, chorioamnionitis, placental insufficiency, spontaneous
abortion, postpartum hemorrhage, and preeclampsia) (47). In addition, evidence
of impact of drug use on the fetus is growing, especially for the combined use
of illicit drugs and alcohol (see Chapter 90) (48). Rates of prescription drug
misuse in pregnancy have increased, and the incidence of neonatal abstinence
syndrome increased 3-fold between 2000 and 2009 (49). Furthermore, with
growing use of marijuana, the effects of marijuana on the fetus and child, which
can include impaired fetal growth, possible effects on other maternal and fetal
outcomes, and screening and intervention for perinatal drug use, are becoming
more important (50,51).
Screening
Unlike those for testing alcohol usage, drug use screening tools to address use
during pregnancy have not been extensively studied. Chasnoff et al. (52)
reported using three questions (have you ever drank alcohol, how much alcohol
did you drink in the month before your pregnancy, how many cigarettes did you
smoke in the month before your pregnancy?) to identify and refer women for a
full drug and alcohol assessment in the context of prenatal exam. In a later
study, Chasnoff et al. (53) demonstrated that the 4P’s Plus, a five-item
instrument derived from the three questions cited earlier, was a reliable measure
with good sensitivity and specificity for substance use (alcohol, marijuana,
heroin, cocaine, and methamphetamines) during pregnancy. The questionnaire
(positive if questions about use during or before pregnancy are affirmative)
asks about Past substance use, use during Pregnancy, and use by Parents and
Partners. The questions are as follows:
Did either of your parents ever have a problem with alcohol or drugs?
Does your partner have a problem with alcohol or drugs?
Have you ever drunk beer, wine, or liquor?
In the month before you knew you were pregnant, how many cigarettes
did you smoke?
In the month before you knew you were pregnant, how many beers/how
much wine/how much liquor did you drink?
With regard to urine toxicology testing, Wright et al. recommend that it should
not be used in place of substance use screening questions.
Brief Intervention
According to the 2008 recommendation of the U.S. Preventive Services Task
Force, there is insufficient evidence to determine the benefits and harms of
screening for illicit drug use among pregnant women. In 2008, the Committee
on Ethics of the American College of Obstetricians and Gynecologists (ACOG)
updated its 2004 recommendations. The ACOG, based on an ethical rationale,
recommends universal screening and brief intervention for alcohol and illicit
drug use (54). Systematic screening and brief intervention for alcohol and drugs
is also recommended by Wright et al. (28). Screening and brief interventions
are usually delivered with protection of confidentiality, notably to enhance
accuracy of screening and establish trust in the clinician–patient relationship.
This confidentiality may be challenged in states where the law requires
physicians to report illicit drug use by pregnant women, and where laws define
this use as criminal behavior. Physicians should also be aware of their state’s
law regarding the reporting of substance use during pregnancy. If thought to
present legal risk, patients could be screened and advised anonymously, for
example, via the Internet or other self-administered materials, though few if
any have been tested in pregnant women.
A recent systematic review identified four randomized controlled trials
testing the efficacy of brief intervention for illicit drugs among postpartum and
pregnant women (55). Three out of four trials tested information technology–
based interventions. Of the four trials, two showed no difference between
groups on substance use (56,57); they also found no effect on use of drug use
disorder treatment. One trial, conducted among 107 postpartum women,
showed a significant effect of a computer-delivered 20-minute intervention on
illicit drug use other than marijuana, but no effect on marijuana use at 4 months
(58). Another trial, aiming at replicating these results, randomized 143
postpartum women to receive a computer-based 20-minute intervention or a 20-
minute inactive control condition and showed a significant intervention effect
at 3 months on 7-day point prevalence of abstinence from illicit drugs
confirmed by urine screens (26.4% abstinence in intervention group, 9.9% in
control group) (59). Thus, brief intervention may have efficacy in this
circumstance but research findings are mixed and limited.
Conclusion and Recommendations
Alcohol
Alcohol has toxic effects on the fetus, and there is currently no safe threshold
identified for its consumption during pregnancy. The current recommendation
for pregnant women, women who might be pregnant, and women who are
trying to conceive is to abstain from alcohol. Given the insufficient evidence to
define any threshold for low-risk drinking during pregnancy, abstinence is the
prudent choice for pregnant women or women who might become pregnant.
Physicians should inform patients of this recommendation. Healthcare
professionals also have an important role in ensuring that patients who have
consumed alcohol do not feel stigmatized. When alcohol consumption did
happen during pregnancy, physicians should be aware of the uncertainty around
the risks of low consumption during pregnancy and explain this to patients (11).
For breast-feeding mothers, recommendations are to avoid consumption of
alcohol or at least not to nurse for at least 2 hours per drink after drinking (that
is, if the mother takes two drinks, at least 4 hours should elapse after the last
drink) (60), as alcohol is concentrated in breast milk, and its use can inhibit
milk production, decrease milk intake by the child, and cause delayed motor
development (61).
Women of childbearing age, including pregnant women, should be screened
using validated tools. Brief, validated instruments are available for screening
pregnant women and those considering pregnancy (T-ACE, TWEAK, AUDIT-
C, 4P’s Plus) and should be used in routine practice. Beyond these tools,
consideration should be given to asking directly about any use and advice given
to abstain during pregnancy given the lack of an imperative to use substances,
and the absence of certainty regarding safe levels of use. Women positive by
screening should then receive a brief intervention. Early intervention strategies
are especially recommended (28,54).
Pregnancy itself, or assessment of alcohol use, may lead women to decrease
or stop drinking. In addition to that effect, brief intervention can decrease risky
use in young women (pregnant or not), and although not extensively confirmed
in the literature to date, can decrease drinking during pregnancy and the risk of
alcohol-exposed pregnancy, may increase abstinence, and may improve fetal
outcomes. Some studies suggest that brief intervention effects are limited to
women who drink the largest amounts. But even if brief interventions are
effective predominantly in the highest risk drinkers, screening, advice to
abstain from alcohol during pregnancy and before a planned pregnancy, and at
least feedback on consequences of alcohol use on the fetus should be included
in routine practice, as preventing alcohol use is the only way to prevent FAS
and other alcohol-related effects on infants. Depending on resources available,
the screening and intervention can be repeated over a few sessions and/or
include the partner, as partner involvement may have beneficial effects. Brief
interventions conducted among pregnant women should include specific
feedback on consequences of drinking on the fetus and infant as well as
medical complications related to alcohol use during pregnancy and
identification of risky situations (and potential coping strategies). In 2010
consensus guidelines sponsored by the Public Health Agency of Canada and
the Society of Obstetricians and Gynecologists of Canada, universal screening
for alcohol consumption for all pregnant women and brief intervention were
given a level II-2B recommendation (evidence from well-designed cohort or
case–control studies; fair evidence to recommend the clinical preventive action)
(46). Parents should be informed of potential legal consequences of reporting
their alcohol use if applicable (eg, loss of parental rights).
Other Drugs
Use of illicit drugs during pregnancy has a negative impact on the course of
pregnancy and on the fetus (47). There is currently insufficient evidence to
determine the benefits and harms of screening for illicit drug use among
pregnant women. Nevertheless, given its potential preventive benefits, it seems
reasonable, if not ethically required, for physicians to give at least feedback on
consequences of use as well as advice to abstain. Experts in prenatal care
recommend interventions (28). Even in the absence of scientific data on
screening and brief intervention efficacy among pregnant women, one would
ask about medications, illicit drug use, and alcohol and tobacco use as part of a
prenatal exam. If a drug use disorder is suspected, women should be referred
for a comprehensive assessment, in order to address substance use severity and
associated psychosocial issues (28,47). For screening, one instrument, the 4P’s
Plus, has been validated among pregnant women. As for alcohol, information
on illicit drug use and tobacco use consequences on the fetus should also be
provided to women of childbearing age. It should be noted that the specific
context of pregnancy and the potential legal consequences will impact the
accuracy of the screening and necessary ingredients of brief intervention, and
clinicians will face ethical challenges, having to balance principles of
beneficence and respect for autonomy as they apply to both women and their
children.
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Trauma Centers, Hospitals, and Emergency

Departments
Arthur F. Weissman and Richard D. Blondell
Individuals with substance use disorders are overrepresented among patients
hospitalized for traumatic injuries (1), or acute medical conditions (2), or who
present to emergency departments (3). Alcohol is the major risk factor for
virtually all categories of fatal and nonfatal injury, including traffic accidents,
burns, drowning, air traffic injuries, occupational injuries, homicides, suicides,
domestic violence, and child abuse (4,5). Patients with comorbid substance use
conditions have worse clinical outcomes, more complications, longer
hospitalizations, and generate increased costs, suggesting an important target
for screening and management (6–8).
Case Finding and Screening
Unhealthy substance use may be suggested by the patient’s chief complaint (eg,
“sustained gunshot in a crack house”), medical records (past delirium tremens
[DTs]), the physical examination (scars from injection or “track marks”), or
laboratory tests (positive urine toxicology). In these instances, no additional
screening is required. However, clinical “case finding” has its limitations. The
rate of detection of substance use disorders by emergency physicians in the
absence of screening protocols is low (9). Clinicians can even fail to recognize
when patients are acutely intoxicated (10).
Validated screening instruments for unhealthy ethanol use include single
screening questions (such as, “how many times in the past year have you had X
or more drinks in a day”, where X is 4 for women and 5 for men) (11), and the
3-item Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)
(12), which is derived from the full AUDIT screen. The single screening
question and the full AUDIT have been modified to screen for drug use. The
classic CAGE questions are not sensitive for detecting current at-risk alcohol
use in the absence of consequences or an alcohol use disorder but are useful to
assess for lifetime alcohol use disorders.
Computerized methods are effective in screening for substance use
disorders (13) and can integrate with existing electronic medical record systems
(14). Because of the stigma associated with substance use disorders, patients
may be more at ease with computer-based screening rather than a face-to-face
encounter with emergency department staff (15). Patients report high levels of
acceptance and ease-of-use with electronic screening but also have
confidentiality concerns (16).
The role of biomarkers to screen for alcohol use disorders has been
reviewed (17). Traditional biomarkers (eg, elevations of liver enzymes) may
suggest the presence of an alcohol use disorder; however, none have sufficient
sensitivity or specificity for routine screening. Highly sensitive tests that detect
alcohol metabolites such as ethyl glucuronide (EtG) and ethyl sulfate (EtS) are
also available. Environmental exposure to ethanol (eg, mouthwash) can result
in false positives, which can be avoided by appropriate laboratory cutoff values
(18). Routine urine, breath alcohol, and/or blood toxicology testing is useful in
trauma patients due to the high rate of alcohol and illicit drug use in this
population (19).
Oral fluid toxicology for substance use is an area of evolving interest. An
oral fluid swab for toxicology may be preferred by staff and patients over a
urine sample as it is faster and perceived as more respectful of patient dignity
(20). Oral fluid may be more suited to qualitative rather than quantitative
testing at present, due to problems with accuracy of results (21).
Online prescription monitoring programs can provide important
information about medications dispensed to the patient. Excessive
prescriptions, dosages, and visits to multiple physicians for controlled
substances can suggest a substance use disorder or diversion. A printout from
the state prescription monitoring program can be an entry point to a discussion
with the patient and a brief intervention (22).
Before implementing routine screening for substance use disorders,
clinicians should be aware of federal patient confidentiality regulations, state
legal concerns, and local health insurance policies (23). Some state laws allow
insurers to deny payment for healthcare costs incurred as a result of
“intoxication” if there has been a positive alcohol or drug test (24).
Clinical Assessment for Risk of Withdrawal
Identifying a severe substance use disorder is of immediate importance, as
treatment to prevent or manage a potentially life-threatening withdrawal
syndrome may be indicated. The biggest risk factor for severe Alcohol
Withdrawal Syndrome (AWS) is a prior history of complicated alcohol
withdrawal, including DTs or alcohol withdrawal seizures (25). A validated
screening tool has been described, the Prediction of Alcohol Withdrawal
Severity Scale (PAWSS) (26), with ten parameters (history of alcohol
withdrawal, alcohol withdrawal seizures, or DTs; previous alcohol withdrawal
episodes, blackouts, concomitant use of other sedative/hypnotic drugs, other
substance use, recent intoxication, an elevated blood alcohol concentration
(>100 mg/dL) on admission, and evidence of autonomic hyperactivity).
However, recent regular heavy drinking is reason enough to monitor for
symptoms, as the PAWSS cannot rule out the development of withdrawal. Licit
or illicit use of sedatives should place the physician on the alert for a sedative
withdrawal syndrome that can also be life threatening (27).
Initial Management of Withdrawal Syndromes
Parenteral thiamine should always be administered as a priority for emergency
department patients with an alcohol use disorder or a history of heavy drinking
before glucose-containing intravenous fluids are given, to prevent the
development of Wernicke encephalopathy (28).
Long-acting benzodiazepines are the medications of choice to prevent and
treat AWS (29). Adjunctive medications, such as dexmedetomidine, a centrally
acting α2 receptor agonist (30) and the short-acting sedative-hypnotic propofol
(31) have been used to control refractory alcohol withdrawal symptoms that
persist after benzodiazepine administration. Patients on dexmedetomidine or
propofol should be monitored in an intensive care setting. Dexmedetomidine
can cause bradycardia, and propofol can result in hypotension or the need for
mechanical ventilation. There is insufficient evidence to support the routine use
of anticonvulsants for the treatment of alcohol withdrawal (32). Phenobarbital
has no proven advantages over long-acting benzodiazepines for treatment of
AWS, and has a less favorable profile in terms of toxicity and therapeutic
index. (33) Withdrawal from short-acting benzodiazepines, such as alprazolam,
may begin within the first 24 hours after hospital admission, whereas
withdrawal from long-acting benzodiazepines or barbiturates may be delayed
for several days; treatment is with a long-acting benzodiazepine taper.
Although opioid withdrawal is not necessarily life threatening, it can
complicate the assessment and treatment of inpatients as well as perioperative
patient care and should therefore be treated (eg, with long-acting opioids such
as methadone or buprenorphine) (34).
New Challenges
A bewildering array of synthetic “designer drugs” has appeared worldwide.
New agents are synthesized in an effort to evade detection by toxicology and
law enforcement. Prominent among these are synthetic cannabinoids (eg, “K2,”
“Spice”), stimulants such as substituted phenylethylamines (“bath salts”), and
synthetic hallucinogens (35–39). Clinical presentations may include
tachycardia, anxiety, agitation, and psychosis (40). The potent new synthetic
opioids U-47700 (or “Pink”) and carfentanil may present with profound
respiratory depression, noncardiogenic pulmonary edema, and hemoptysis (41).
These drugs are readily available and marketed to adolescents, young adults,
and military personnel (42). Commercially available toxicology screens are
usually unable to detect these drugs, adding to the diagnostic challenge. The
political impetus in the United States to legalize marijuana use presents special
problems for screening. There are conflicting data on the effects of marijuana
use on cognitive development and mental illness (43). There is considerable
evidence, however, for serious health risks with marijuana, including cannabis
use disorder, sensitizing the developing brain to other drugs (the “gateway”
effect), trauma (including fatalities) due to impaired driving, and associations
with poor educational and occupational performance (44). People who use
substances may have a lower perception of marijuana risk that is discordant
with physician perspectives (45). Notwithstanding the decreased perception of
risk that has accompanied marijuana deregulation, as is the circumstance with
the legal substance alcohol, physicians should continue to screen patients, and
especially young patients, for cannabis use, due to these significant health risks
(46).
Intervention and Discharge Planning
An acute medical problem or the pain from a traumatic injury can provide a
“moment of clarity” and diminish the usual patient denial of problem drinking
or illicit drug use. If approached at the right time, hospitalized patients can be
surprisingly receptive toward an intervention designed to address an alcohol or
drug condition.
Although most physicians are capable of addressing alcohol and drug
problems with their patients if given proper training, they are often
appropriately focused on providing acute medical or surgical care. Therefore,
other members of the hospital team may need to discuss a substance use
disorder treatment plan with the patient prior to hospital discharge. Resources
include social workers, substance use disorder consultation services (47),
nurses trained to deliver interventions (48), lay people trained as “Health
Promotion Advocates” (49), and peers in recovery (50).
Efficacy of Brief Intervention
There are conflicting reports about the effectiveness of brief interventions in
emergency departments, trauma centers, and inpatient settings, with some
reports suggesting a positive benefit (51), others suggesting a lack of benefit
(52), and others inconclusive (53). As with screening for substance use
disorders in primary care settings, the best evidence is for screening for
unhealthy alcohol use. A recent narrative review suggests that brief
interventions can be associated with a reduction in alcohol consumption, binge
drinking, and alcohol-related negative consequences (including future
emergency visits and hospitalizations, driving while intoxicated, and alcohol-
related injuries) though it called for additional research, and subsequent
systematic reviews have found modest efficacy, at best (54). A review of
randomized, controlled studies of screening and brief intervention in a variety
of clinical settings found that evidence was inconclusive for any benefit with
illicit drug use; (55) a large multisite randomized controlled trial of screening
and brief intervention for adult illicit drug use in the emergency department
showed no evidence of efficacy (56).
Even when the patient admits to a serious alcohol or drug condition and is
willing to follow recommendations, it is not always easy to coordinate
treatment. Referral for treatment with opioid agonist medication requires a
qualified prescriber and may necessitate a lengthy and complex prior
authorization process with an insurance company, which can take days, or
present challenges in finding a program or prescriber that can see the patient
immediately after hospital or emergency department discharge. These delays
serve the financial interests of insurance companies or health systems and may
reflect societal stigma while exposing the patient to an increased risk of relapse,
overdose, and death at a critical moment (57).
The Physician’s Role
Many clinicians are reluctant to screen their patients for unhealthy substance
use (58). Physicians cite competing priorities (59) and not enough time (60) as
reasons for this reluctance. However, in these high prevalence settings (ED,
hospital, and trauma centers), patients should be screened for unhealthy
substance use (eg, with brief validated tools and toxicology) and should be
counseled to cut down or quit in the context of a teachable moment. The
absence of a proven benefit for screening and brief intervention for illicit drug
use does not mean that identifying unhealthy substance use is not important
(61). Brief interventions may have an improved effect when repeated over time
(62), and patients should be offered additional treatment if the patient is ready,
and medication to manage withdrawal symptoms, if it is indicated.
Identification of unhealthy substance use is also critical as part of the diagnosis
and management of other disorders, especially when potentially addictive
medications might be prescribed or when symptom etiology needs to be
properly diagnosed. What else can busy physicians do to help their patients
with unhealthy substance use? First: do no harm. The United States is in the
midst of an epidemic of opioid use disorder, overdose, and death that has been
driven largely by inappropriate opioid prescribing by physicians (63). When
contemplating prescribing controlled substances, physicians need to screen
patients carefully for substance use and disorders and associated risk factors,
and to review urine toxicology and prescription monitoring databases. These
data are vital for mitigation of the risks of iatrogenic substance use disorders
and drug diversion (64). Secondly, although there has been a change in the
doctor–patient relationship away from paternalism to a more “patient-centered”
model with shared decision-making, physician recommendations can still carry
weight with patients (65). A critical role for the physician would be to evaluate
data obtained at screening, and then to express concern to the patient about
risky substance use, and then to make a clear recommendation (ie, a brief
intervention). Thirdly, physicians can demonstrate an important leadership role
within their own practice settings by screening their patients for unhealthy
substance use behaviors. Lastly, physicians can have a system-wide impact by
advocating for universal patient screening for unhealthy substance use, for
example, by integrating screening into triage and existing electronic medical
record systems, and by incorporating screening and brief counseling training
into resident physician education (66).
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Implementation of Screening and Brief

Intervention (SBI) in Clinical Settings Using
Quality Improvement Principles
Emily C. WilliamsKatharine A. Bradley
Despite evidence-based recommendations that alcohol screening and brief
intervention (SBI) be routinely implemented in primary care settings, efforts to
implement SBI have been disappointing. However, some integrated healthcare
systems are making progress toward implementation. One example is the
Veterans Health Administration (VA). We provide a retrospective analysis of
VA’s implementation based on a comprehensive conceptual model of
dissemination of innovations in healthcare settings (Fig. 22-1).
Figure 22-1 Factors that influence the success of
implementation. (Adapted from: Greenhalgh T, et al.
Diffusion of innovations in service organizations: systematic
review and recommendations. Milbank Q. 2004.82:581-
692.)
Greenhalgh’s model outlines the importance of the nature of an innovation, as

well as the characteristics of both the user system and innovators, and the
linkage between the two. Innovations are more likely to be successfully
implemented if they are simple, relevant to the user, and easily transferable.
The setting in which implementation occurs—the user system—is also central
to the success of innovations. Important components of user systems that help
determine the success of innovations include the following: system antecedents
(eg, quality improvement resources), system readiness (eg, institutional
pressures for change), characteristics of adopters (eg, motivation, values,
understanding of the innovation), the implementation process (eg, support from
leadership), and evaluation and feedback that allows the system to address
consequences of implementation. Innovators typically consist of formal or
informal “teams” of experts (“knowledge purveyors”) and leaders able to
actualize change (“change agents”) with access to resources required to
implement an innovation. Efforts to implement innovations are also most
successful when there is strong linkage between the innovators and the user
system, both during the development of an innovation and throughout the
implementation process.
The VA healthcare system had undergone several quality improvement
initiatives, which served as system antecedents that provided an essential
foundation for SBI implementation. These include a nationwide electronic
medical record (EMR) with embedded clinical reminders, a system of
nationwide performance measures that incentivize recommended care and are
linked to financial incentives for network directors, and data systems (medical
record reviews and patient satisfaction surveys) to monitor performance. The
VA also had condition-specific Quality Enhancement Research Initiative
centers, including one focused on substance use disorders (SUD QUERI).
These centers developed research programs to identify important gaps in the
quality of VA care, evaluate interventions to address identified gaps, and
develop and evaluate strategies for implementation. Findings from the VA’s
Large Health Study of Veterans suggesting unmet need among patients with
unhealthy alcohol use in VA created pressure from the US Congress for VA
leadership to do more to recognize and treat unhealthy alcohol use and served
as the impetus for linkage between VA quality managers and SUD QUERI
researchers. Via this linkage, the VA built upon its existing quality
improvement structures to implement national performance measures for and
electronic clinical reminders to prompt and document both screening and brief
intervention. The QUERI infrastructure provided ongoing core funding for
implementation research after initial funding of innovations by research (ie,
development and pilot testing of EMR clinical reminders). However, clinician
education regarding SBI was delegated to local quality and clinical leaders with
variable expertise and interest. Initially, the QUERI infrastructure—with a rapid
grant-funding mechanism coupled with core funding—enabled formative
evaluations that identified gaps in SBI quality. Formative evaluations also
highlighted the importance of ongoing attention to the educational needs of
clinicians (“adopters”) and feedback to clinicians regarding performance.
While attention is now being focused on identifying best practices and
performance measures that incentivize high-quality SBI, changes in the QUERI
infrastructure, including moving away from condition-specific funding for
implementation research (and thus closing the substance use disorders QUERI
center), have decreased ongoing quality improvement research.
Since SBI implementation in VA, the Affordable Care Act increased the
readiness of other US healthcare systems to implement SBI by making alcohol
screening and brief intervention core preventive benefits. Similar quality
improvement processes to those used in VA are being used in other healthcare
systems—such as Kaiser Permanente. Efforts in Kaiser Permanente specifically
focus on incorporating implementation into existing quality improvement
structures, such as performance monitoring and “Plan Do Study Act” or
“PDSA” cycles, which are currently used by local clinics to optimize care
quality. Cross-system implementation research could enable identification of
key determinants of implementation success, as measured by delivery and
quality of care provided.
SUGGESTED READING
Greenhalgh T, Robert G, Macfarlane F, Bate P, Kyriakidou O. Diffusion of innovations in service
organizations: systematic review and recommendations. Milbank Q. 2004;82(4):581-629.
Jonas DE, Garbutt JC, Amick HR, et al. Behavioral counseling after screening for alcohol misuse in
primary care: a systematic review and meta-analysis for the U.S. preventive services task force. Ann
Intern Med. 2012;157(9):645-654.
Williams EC, Johnson ML, Lapham GT, et al. Strategies to implement alcohol screening and brief
intervention in primary care settings: a structured literature review. Psychol Addict Behav.
2011;25(2):206-214.
Williams EC, Achtmeyer CE, Young JP, et al. Local implementation of alcohol screening and brief
intervention at five Veterans Health Administration primary care clinics: perspectives of clinical and
administrative staff. J Subst Abuse Treat. 2016;60:27-35.
Mertens JR, Chi FW, Weisner CM, et al. Physician versus non-physician delivery of alcohol
screening, brief intervention, and referral to treatment in adult primary care: the ADVISe cluster
randomized controlled implementation trial. Addict Sci Clin Pract. 2015;10:26.
Chi FW, Weisner CM, Mertens JR, Ross TB, Sterling SA. Alcohol brief intervention in primary
care: blood pressure outcomes in hypertensive patients. J Subst Abuse Treat. 2017;77:45-51.
Bobb JF, Lee AK, Lapham GT, et al. Evaluation of a pilot implementation to integrate alcohol-
related care within primary care. Int J Environ Res Public Health. 2017;14(9):1030.
Screening for Unhealthy Alcohol Use in the

Elderly
James W. Campbell
Epidemiology
The population of elders in the United States is growing dramatically. The 2010
census projects nearly 50 million Americans over the age of 65 by 2020.
Current projections are that by 2050, 83 million Americans will be elderly. The
population over 65 will rise from 12% in 2000 to over 20% of the population
by 2050 (1). Alcohol use disorder is present in 6%-11% of older persons
admitted to hospitals (2). A common misconception—that the prevalence of
alcohol use disorder is low—partially stems from the decline in any
consumption, as 60% of men and 30% of women report a decline in alcohol use
after age 65. Alcohol use disorder estimated to be the third most common
psychiatric disorder among elderly persons. Prevalence is estimated to be
approximately twice as high in men as in women (3). The elderly represent an
underrecognized population at risk for alcohol use disorder (4). Clearly,
detection is suboptimal in elders and especially in elderly women with only
37% of those with alcohol use disorder being detected by physicians in training
(5). Only 27% of persons under 60 years of age with alcohol use disorder were
identified by their healthcare providers, and only 21% of those over 65 years of
age were identified. Estimates are as many as three-fourths of older adults with
alcohol use disorder admitted to hospitals are not diagnosed. Table 22-5
summarizes rates of elderly with alcohol use disorders in specific clinical
settings.
TABLE 22-4-1 Rates of Alcoholism in Elderly Clinical

Settings
Diagnosis
Diagnostic definitions are challenging in this population, and screening tools
have to be appropriate for the biopsychosocial reality of elderly persons. Older
adults with alcohol use disorder are classified as late onset if they present after
age 65. It is estimated that in the United States, one-third of older adults with
alcohol use disorder are late onset, or ~700 000 individuals. Care must be taken
in labeling a person late onset, as many older individuals may have had
undetected symptomatology in their remote past. The older cohort is especially
adverse to the label of “alcoholism” and is more amenable to accepting that
their alcohol intake is negatively affecting their health. Screening for unhealthy
alcohol use is a more appropriate goal for primary care. Elders are more likely
to be widowed, retired, and socially isolated, all contributing to poor alcohol
use disorder detection rates. In particular, the Diagnostic and Statistical Manual
of Mental Disorders (DSM) criteria include consequences less likely to occur in
elders (6). Of the criteria for alcohol use disorder, at least three are affected by
age; failure to meet obligations at home, school, or work; and problems with
significant others. The presence of alcohol use disorder is significantly
impacted by pharmacokinetic changes that occur with aging, resulting in more
consequences at lower quantity and frequency of alcohol intake. Although
consumption is not a criterion, this change can interfere with recognition of
tolerance, which can be present as drinking less and having the same effect. For
all these reasons, definitions for alcohol use disorder in the elderly and tools to
screen for it need to be approached from an age-sensitive perspective. Key
elements of an elderly sensitive approach include (a) increased awareness of
alcohol use disorder symptoms that can be attributed to age-related changes
that change, (b) increased awareness of alcohol use disorder symptoms that can
be attributed to diseases common in elders, and (c) increased awareness of
alcohol use disorder symptoms that are age adjusted or specific to elders.
Elders have altered pharmacokinetics that impact on the metabolism of
alcohol. They have proportionally more body fat and less water than younger
individuals, and therefore achieve higher blood alcohol concentrations with
ingestion of lower quantities of alcohol. They also have significant use of
pharmacological agents, many of which have narrow therapeutic windows and
concentrations significantly altered by alcohol. These differences between
elders and younger people lead to differing effects of alcohol use and
manifestations of alcohol use disorder.
Different Clinical Manifestations in the Elderly
Older individuals are less likely to be screened and are more likely to have their
symptoms attributed to aging or to diseases common in elders than suspected as
an alcohol problem. Table 22-6 summarizes factors leading to low detection
rates. An older person’s alcohol use disorder has a great diversity of clinical
presentations. In addition, alcohol’s impact on or exacerbation of common
diseases is likely to be overlooked in older persons. Many elderly with alcohol
use disorder present as a new medical diagnosis or an exacerbation of a chronic
medical condition. Table 22-7 reviews diseases common in elders in which
alcohol is a possible etiological factor or a significant contributor to worsening
disease.
TABLE 22-4-2 Age-Related Factors Affecting Rate and

Impact of Alcoholism
TABLE 22-4-3 Clues to the Presence of an Alcohol Use

Disorder Attributed to Coexisting Diseases with High
Prevalence in Older Persons
Screening is improved by use of geriatric-specific screening instruments or
standard tools that are age adjusted for number of responses that indicate a
positive screen. Asking typical quantity and frequency and heavy drinking
occasions can be helpful, adjusting the definition of a heavy drinking episode to
4 or more standard drinks. Table 22-8 summarizes a few of the more common
tools. Longer tools tend to focus on disorder and since they are geriatric
specific, they can be useful, but those tools do not necessarily identify elders
with risky consumption and no consequences. The comorbidity alcohol risk
evaluation tool is helpful to identify elders at risk. A study done at UCLA
demonstrated 34.7% of persons over 60 with any alcohol use were at risk;
61.9% were at risk due to alcohol use and comorbid illness; 61% were at risk
due to alcohol use and simultaneous use of high-risk medications; and 64.3%
were at risk due to alcohol behaviors (7). AUDIT-C is helpful for primary care
screening where time is limited and in settings where screening approaches are
unlikely to be altered to be specific to age and other characteristics. A brief
screen facilitates primary care intervention.
TABLE 22-4-4 Test Sensitivity and Specificity for

Alcohol Use Disorder when Used in Older Individuals
aAUDIT-C had similar psychometric properties to AUDIT.
Data from Buchsbaum DG, Buchanan BA, Welsh MA, et al. Screening for drinking in the elderly using
the CAGE questionnaire. J Am Geriatr Soc. 1992;40:662; and Widlitz M, Marin DB. Substance abuse in
older adults: an overview. Geriatrics. 2002;57:29.
Use of lab tests to aid in the diagnosis is of limited utility. Tests such as mean
corpuscular volume and gamma GT already nonspecific in younger persons
have even worse specificity in older individuals. Carbohydrate-deficient
transferrin likewise has not been validated as a screening tool in elders.
Impact of Alcohol on Health
In elders, the negative consequences of excessive alcohol use are even more
severe than in younger populations. Neurocognitive impairment already
common in this population is worsened by excessive drinking. It is estimated
that as many as 10% of patients with diagnosed Alzheimer disease may have an
alcohol-associated dementia or a dementia presentation worsened by alcohol
consumption (8). Many health and sensory realities of aging also make
manifestations of alcohol use disorder more severe. A classic example, hip
fracture, is associated with alcohol use through not only an increase in falls but
also by a direct effect by exacerbating osteoporosis (9). Combined with
smoking, elderly adults who drink heavy amounts were had 36% faster
cognitive decline compared to elders who drank lower amounts and did not
smoke (10).
Intervention
Mechanisms to guide a patient into treatment are similar to other age groups,
and brief office or urgent care/emergency department intervention can be
effective, at least for those without a moderate to severe disorder. Modification
to the approach is valuable as previously stated, and the nonlabeling approach
is more readily accepted. In addition, the realistic benefits are different. As
opposed to job and legal issues, older patients are more concerned with health,
disability, and more particularly with the ability to live independently and
interact with loved ones. The value of an elderly specific treatment milieu or
group is debated. Although logical, no evidence exists to support differential
benefit of an elderly specific treatment environment or group.
Summary
In summary, the age wave is upon us, and rates of alcohol use disorder and
other drug use—especially prescription drug misuse is substantial. The
diagnosis is often missed as a result of poor screening techniques,
underreporting, age bias, and misattribution of alcohol-related health issues to
either aging or to other diseases common in elders. Appropriate screening tools
do exist and are useful, though markedly underused. In addition, brief
intervention and standard treatment strategies, and connection to sober social
networks such as Alcoholics Anonymous (AA), can be effective. The health
yield of sobriety is tremendous, since heavy alcohol use is even more
dangerous when it occurs in older persons who have less physiological and
psychological reserve than do younger people. Finally, recovery rates are at
least as favorable if not higher in elders with alcohol use disorders as in
younger populations.
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ACKNOWLEDGMENTS
This work was supported in part by grants K23DA037913 from the National
Institute on Drug Abuse to Dr. Massey and K23AA017508 from the National
Institute on Alcohol Abuse and Alcoholism to Dr. Zgierska.
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CHAPTER 23
Laboratory Assessment
Jessica S. Merlin, Elizabeth A. Warner and Joanna L.
Starrels
CHAPTER OUTLINE
Introduction
Approach to Testing
Substance-Specific Tests
Conclusions
INTRODUCTION
Laboratory testing can play a key role in the diagnosis and evaluation of
substance use disorders. Testing can directly identify substances in body fluids
or tissues, and in some cases, it is useful for identifying indirect markers of
substance use. Accurate interpretation of laboratory findings requires knowledge
of the limitations of the specific tests being used, including the possibility of
false-positive and false-negative results (1).
In our experience, there are four main clinical scenarios in which laboratory
testing is most useful: to identify substances associated with overdose or trauma
in an emergency setting (2), to assist in the initial diagnosis of a substance use
disorder, to monitor abstinence in patients in treatment for a substance use
disorder, and to monitor risk and treatment adherence in patients who are taking
prescribed controlled substances. Laboratory testing is not recommended for
universal screening for unhealthy substance use. Workplace testing for safety-
sensitive occupations is beyond the scope of this chapter.
Given the purpose of this text, this chapter focuses on laboratory testing for
the purposes of assisting with the diagnosis and treatment of substance use
disorders. However, many of the principles reviewed here also apply to
monitoring individuals who are prescribed controlled substances (eg, long-term
opioid or benzodiazepine therapy).
APPROACH TO TESTING
Interpretation of Test Results
Although tests for identifying substance use are widely available and reasonably
simple to perform, skill is required in the interpretation of the resulting data.
Laboratory results should always be interpreted in the clinical context. The
clinician should know which substances are detected by the tests ordered and
how long the substance is detectable after use. It is critical that clinicians faced
with interpreting test results that are unexpected or inconsistent with the patient’s
report understand the limitations of testing, such as false-positive and false-
negative results.
Body Fluids for Testing

Virtually any body fluid or tissue can be assayed for substances of interest, but
for practical purposes, such testing is limited to specimens that can be obtained
in a reasonably noninvasive manner. The most commonly used sources for
clinical testing are urine and blood. Other sources are oral fluid, sweat, hair,
breath, and meconium (3).
Urine
Urine is the most common source for testing because it can be collected easily
and noninvasively, and urine toxicology tests are widely available. A large
quantity is available and substances are often present in high concentrations.
However, clinicians must be aware that urine specimens are easily diluted,
adulterated, or substituted (4). Commonly used parameters to ensure a valid
specimen include appearance, temperature, pH, specific gravity, and creatinine
concentration.
Blood
Blood testing can be more useful and accurate than urine testing for identifying
recent ingestion, such as in acute overdose or intoxication states, or when it is
critical to determine the blood level such as in acetaminophen poisoning. In
addition, blood is less likely to be adulterated or substituted than urine. However,
alcohol and other substances are generally present in the blood for much shorter
periods than in the urine. Also, venipuncture requires training and is invasive.
Obtaining blood or other specimens may be necessary in patients who do not
easily produce urine, such as those on dialysis.
Oral Fluid
Oral fluid, which is a mixture of saliva, fluid from gingival crevices, and food
remnants, can be used to detect substance use (5). Oral fluid collection is
noninvasive, and directly observed collection does not involve the same privacy
issues as with urine collection. Adulteration during sample collection is less
likely with oral fluid than with urine. Substance concentrations in oral fluid
mirror circulating concentrations in plasma and can be used to assess for recent
substance use. Similar to blood, a disadvantage of oral fluid testing is that
substances are present in oral fluid for a shorter period of time than in urine.
Further, differences in collection technique can affect drug concentrations in oral
fluid. Contamination of oral fluid from recently smoked or ingested drugs, and
even mouthwash, can affect measurements in oral fluid (6). Waiting for up to 30
minutes before sample collection may improve the accuracy of results,
particularly when the mouth is dry. Chewing gum and citric acid candy
stimulates saliva production but can alter salivary pH and drug concentrations
(7).
Sweat
As many substances are secreted into sweat, patches can be applied to the skin to
absorb sweat and measure secretion. The measurement represents secretion of a
substance over an extended period of time while the patch is in place, for
example, over a week. However, sweat can be collected in only relatively small
amounts, and quantification of substance levels in sweat is limited by the
inability to quantify the total amount of sweat secreted (8).
Hair
Hair testing may be more applicable to forensic or research study testing than to
clinical or workplace testing. Hair can be collected easily and noninvasively, and
adulteration and substitution are less likely than with urine. Substances are
deposited from the blood into the hair during keratinization and diffused into the
hair shaft from the surrounding skin tissues and remain in the hair shaft in a
fixed position indefinitely (9). Thus, hair analysis can provide a history of the
pattern of substance use over a long time span. Hair testing is not helpful in
assessing acute intoxication, because significant deposition requires 1-2 weeks.
Additionally, substance concentration in hair varies by pigmentation, cosmetic
treatments, and environmental contamination.
Collection Procedures
Proper collection and processing of specimens are essential for accurate results.
Universal handling precautions are recommended for all specimens. For
individuals prescribed long-term controlled substances (eg, opioids or
benzodiazepines), the last dose taken should be noted, so results can be
interpreted in the context of the time of ingestion. It is important to confirm the
identity of the person supplying the specimen and to properly label the
specimen. Chain-of-custody regulations in forensic or workplace testing have
been developed to prevent specimen misidentification, especially when the
testing has legal implications. However, it is not routine to implement chain-of-
custody procedures when testing is done for clinical purposes.
Specimen Validity Testing

Since specimens can be altered or diluted, testing for urine specimen validity is
required in federal workplace testing (10) and may also be helpful in clinical
settings. There are several commonly used measures of specimen validity. Urine
can be tested for creatinine concentration, specific gravity, and pH to ensure that
these are within the normal range of human urine. Very dilute specimens with
creatinine concentrations <5 ng/mL or specific gravity <1.003 suggest specimen
tampering. The temperature of recently collected urine specimens should
approximate body temperature, specifically, 90°F to 100°F within 4 minutes of
collection; strips outside the collection cup can determine this easily. Federal
workplace testing mandates testing every urine specimen for adulterants; this is
not done routinely in clinical care.
Laboratory Methods
Screening Immunoassay Tests
The initial procedure for testing is usually a screening urine immunoassay.
Typically, laboratories offer panels that include multiple tests for commonly used
substances. Immunoassays are inexpensive, are easily automated, may be
performed at the point of care (see “On-Site Testing,” below), and yield rapid
results. In these tests, antibodies are designed to detect specific targets, such as a
class of drugs, a parent substance, or a metabolite.
A major limitation of immunoassays is cross-reactivity (11). The antibody
can interact with substances other than the targeted substance, yielding a false-
positive result (Table 23-1). Manufacturers of commercial immunoassays use
different antibodies, and not all assays share the same cross-reactivities (12). The
manufacturers of these tests publish package inserts that report the concentration
above which substances are detected (see “Cutoff,” below). The inserts also list
structurally similar substances that have been identified to cross-react with the
assay and thus cause false-positive results. The inserts are available from the
laboratory, and many are available online. The cross-reactivity information
usually applies to the parent substance and does not include cross-reactivity
information on endogenous metabolites. Therefore, this information should be
interpreted with caution, recognizing that metabolites of a compound may have
cross-reactivity even though the parent compound does not.
Table 23-1
Another major limitation is that immunoassays that are designed to detect a class
of substances such as opiates or benzodiazepines have variable sensitivities for
detecting different substances within the class. For example, opiate panels are
often designed to detect morphine and codeine and are less sensitive for
detecting semisynthetic and synthetic opioids.
Confirmatory Tests
Confirmatory testing uses gas or liquid chromatography to separate the
substances in the specimen, followed by mass spectrometry or tandem mass
spectrometry to identify the substances. These techniques can specifically
identify and quantify the concentration of substances or metabolites. In our
experience, there are three situations in which confirmatory testing is most
useful. First, it is useful to confirm an immunoassay result that returned positive
for an unexpected substance (eg, that the patient does not report taking). Second,
it is useful to identify specific substances or metabolites within a class that was
detected in an immunoassay (eg, which opioid is present). Third, it is useful to
detect an expected substance (eg, a prescribed opioid) that was not detected or is
not detectable in an immunoassay.
In clinical care, confirmatory testing is unnecessary if the patient report is
consistent with the immunoassay result. Confirmatory testing is more expensive
than immunoassay testing, and not as widely available. Thus, specimens may
need to be sent out to a reference laboratory, causing delays that preclude its use
for clinical decision-making in urgent clinical scenarios.
For workplace or forensic testing, confirming a positive immunoassay by
chromatography and mass spectrometry is required before reporting a test as
positive. This is because although confirmatory testing is relatively expensive
and time-intensive, it is significantly less susceptible to false-positive and false-
negative results and can definitively identify specific substances.
Cutoff
For both immunoassay and confirmatory tests, a cutoff or threshold is a defined
concentration of an analyte in a specimen at or above which the test result is
reported as positive. Below the cutoff, the result is reported as negative. The
factors that are considered in establishing a cutoff include the goals of testing,
the sensitivity of the assay, the desired duration of detection of substance use,
and data from pharmacological studies. Lower cutoff levels are associated with a
higher sensitivity and with longer detection times but also cause more false-
positive results. Table 23-2 lists approximate duration of detection time from the
time of last use, using commonly used cutoffs. If a substance is present in a
specimen in a concentration lower than the defined cutoff, the test result will be
reported as negative. When this occurs with a screening test, ordering an
additional confirmatory test may be helpful.
Table 23-2 Approximate Detection Time Using

Screening Urine Immunoassays (With Commonly Used
“Cutoffs” and Metabolites)
aThe duration of detection is variable and depends on dose, route of administration, pattern of use,
laboratory cutoff, metabolites tested, and individual metabolism.
On-Site Testing
Point-of-care or on-site testing refers to tests that are performed outside of a
central laboratory. Commercially available immunoassay kits are available to
test urine or oral fluid for commonly used substances. These tests are performed
at the time of specimen collection. The assays are rapid, are easy to perform, and
require little training but may be more expensive than tests performed in large
numbers by central laboratories. The interpretation of these tests can be
subjective, making them operator dependent. Most studies find that point-of-care
testing is fairly reliable, with results comparable to automated immunoassays
(13). However, cutoffs are not standardized among tests, and all are subject to
false-positive and false-negative results. As these point-of-care tests are designed
for use as screening tests, many manufacturers recommend that any positive
results be confirmed by more specific laboratory methods. Nevertheless, because
the rapid and reasonably reliable results allow for prompt clinical decision
making, many of these tests have been accepted for use in clinical settings
without confirmation. Confirmatory testing should be considered when the test
result and clinical situation do not concur, such as when a patient denies use of a
substance detected on the screening test, if test results would lead to a change in
the treatment plan.
Federal Regulations
The Substance Abuse and Mental Health Services Administration (SAMHSA),
an operational division of the U.S. Department of Health and Human Services,
oversees drug testing of federal workers (10). The U.S. Department of
Transportation (DOT) requires drug and alcohol testing of safety-sensitive
transportation employees in aviation, trucking, mass transit, railroad, pipelines,
and other transportation industries (14). Both agencies have developed extensive
guidelines for specimen collection, chain-of-custody procedures, specimen
validation, and testing procedures. DOT and federal workplace testing must be
done in laboratories certified by the National Laboratory Certification Program.
The 2008 SAMHSA workplace urine drug test panel includes marijuana
metabolites (tetrahydrocannabinol, THC), cocaine metabolites, opiate
metabolites, phencyclidine (PCP), and amphetamines (10).
Clinical Laboratories
Clinical laboratories perform alcohol and other substance testing for diagnostic
purposes. Since clinical laboratories can select which substances to include in
their test panels, the assays may vary among laboratories. Therefore, in addition
to reading the package insert, consulting with the laboratory’s clinical
toxicologist can be very helpful in interpreting results. Specimens obtained for
clinical use, however, are not subject to the same collection and testing
requirements used in federal workplace testing. Clinical laboratories are not
required to use the cutoffs chosen for workplace testing for federal workers.
SUBSTANCE-SPECIFIC TESTS
Alcohol
Alcohol Use
Laboratory testing to assess for alcohol intoxication relies on measurement of
ethanol from body fluids. These measurements can confirm recent alcohol intake
but do not necessarily determine impairment, because some individuals develop
tolerance to the effects of alcohol. Both blood and breath tests can estimate a
person’s alcohol ingestion.
Blood alcohol concentration detects alcohol use within the preceding few
hours. Testing for alcohol levels in blood can be done using enzymatic analysis
or gas chromatography of the headspace. Specimens for venipuncture should be
drawn using an alcohol-free antiseptic. The enzymatic analysis measures the
amount of nicotinamide adenine dinucleotide formed during oxidation of
ethanol; this may produce falsely elevated readings in the presence of
isopropanol, methanol, and ethylene glycol. High levels of acetone, such as
found in diabetic ketoacidosis or starvation, can be metabolized to isopropanol,
giving falsely elevated ethanol levels by the enzymatic analysis (15).
In the headspace analysis, a specimen of blood partially fills a Vacutainer
tube. Ethanol equilibrates between the blood and the air space (headspace) above
the liquid. A portion of the vapor from the tube is injected onto a
chromatographic column and then quantitated (16). Although gas
chromatography is considered the gold standard for measuring ethanol in
forensic laboratories, many clinical laboratories use enzymatic methods.
Most states define intoxication based on whole-blood alcohol levels alone,
and not on clinical examination; the most commonly used alcohol levels are 80
or 100 mg/dL. Clinical laboratories, however, measure ethanol in serum or
plasma. Because the water content of serum is higher than that of whole blood,
the same specimen will show a higher level of ethanol in serum than in whole
blood (17). An estimate of the ratio of serum to whole blood is 1.14/1.00. If a
clinical specimen of serum or plasma is used to estimate whole-blood levels, the
appropriate correction needs to be calculated.
Less invasive means of detecting the blood alcohol concentration include
analysis of alcohol in the exhaled air. Breath alcohol testing is usually done in
traffic law enforcement and DOT testing. The alveolar concentration of ethanol
is most accurately measured when the subject takes a deep breath and exhales,
with the measurement taken in the last third of the breath. Failure to obtain a
deep breath specimen can lead to an underestimate of blood alcohol level (18).
The ratio of blood to breath concentration of alcohol is ~2100:1, though this
probably underestimates venous levels by about 10% (18). In the United States,
breath alcohol concentration is usually reported in grams per 210 L, so that a
breath level of 0.1 g/210 L is equivalent to a whole-blood alcohol level of 100
mg/dL. In order to allow clearance of any ethanol that may be in the mouth, the
DOT requires retesting after a 15-minute waiting period if the initial test is 0.02
g/210 L or greater (14).
Oral fluid can also be used to estimate serum ethanol concentration, using a
point-of-care collection testing device. The concentration of ethanol in saliva
theoretically is similar to that in serum, although salivary alcohol levels do not
correlate as well with breath tests in measuring blood alcohol levels (19).
Patients with chronic alcohol ingestion may have difficulty producing adequate
oral fluid samples. This may be explained by some degree of parotid dysfunction
related to chronic alcohol use.
Urine testing for alcohol provides a qualitative marker of recent alcohol
ingestion, although it does not measure intoxication. The presence of alcohol in
the urine suggests alcohol intake within the preceding 8 hours. However, urine
concentrations are variable compared to blood levels and are related to the length
of time the urine has been in the bladder, so quantitative measures of alcohol
levels in the urine are difficult to interpret. Ethyl glucuronide (EtG), a direct
metabolite of alcohol, has a slower clearance rate in the urine compared with
ethanol (20) and can be detected in the urine from 24 hours up to 5 days
depending on the amount of alcohol ingested (21). EtG can be detected in the
urine even after consumption of relatively small amounts of alcohol, including
when the subject uses hand sanitizers or alcohol-containing mouthwashes (22).
In addition, EtG is detected in patients with glucosuria. Because it is difficult to
reliably determine the source of EtG, there is potential for false-positive results
in EtG testing in clinical and justice system settings (23). Ethyl sulfate (EtS) is
another metabolite of ethanol that can be detected in urine if tests are available,
alone or in combination with EtG. EtS testing also has the advantage of a long
detection window, up to 3-4 days after consumption.
Alcohol Biomarkers
While measurement of blood alcohol concentration is useful to identify recent
ingestion, several blood alcohol biomarkers can be used to predict alcohol-
related health problems (24). Blood tests that are considered biomarkers for
alcohol use disorder include gamma-glutamyltransferase (GGT), aspartate
aminotransferase (AST), and erythrocyte mean cell volume (MCV).
Of these tests, the GGT is the most sensitive marker for detecting alcohol
use disorder (25). GGT levels are elevated in ~75% of persons with diagnosed
alcohol use disorder, ~50% of patients hospitalized for alcohol-related problems,
and ~30% of people who drink heavy amounts and have related problems. It is
important to note that the GGT is not specific for alcohol use disorder and is also
elevated in patients with fatty liver or obstructive liver disease and in those using
certain medications, including anticonvulsants. Given these limitations, the GGT
is not useful for universal screening. GGT has some utility in monitoring
abstinence and relapse. GGT levels generally are reduced by half after ~2 weeks
of abstinence and can return to normal after 2-4 weeks of abstinence. One study
found that using a 30% increase in baseline GGT values to detect relapse lacked
sensitivity, but had high specificity of 92% in men and 89% in women (26).
The MCV (mean corpuscular volume), a measurement of red blood cell size,
increases with chronic heaving drinking. With abstinence, the MCV will
decrease, but it may take several months. MCV elevation is not specific to
alcohol-related conditions; other causes include chronic liver disease,
hypothyroidism, folate deficiency, and megaloblastic disorders. MCV takes
longer to decline than GGT does, and is less helpful in monitoring patients in
treatment for alcohol use disorder (27).
Another biomarker for heavy alcohol use is carbohydrate-deficient
transferrin (CDT). In the setting of heavy alcohol ingestion, the glycosylation
process of transferrin is impaired, resulting in CDT (28). Drinking four to seven
standard drinks (about 50-80 g of alcohol) per day for a week is required to
elevate CDT levels. The half-life of CDT is ~15 days. CDT levels are usually
measured as the %CDT/total transferrin, to adjust for variability in transferrin
levels. A %CDT greater than 2.6% is indicative of heavy alcohol use. The main
advantage of the %CDT over GGT is greater specificity. However, there are
other etiologies of elevated CDT including advanced liver disease and genetic
variations of transferrin. In one study that examined simultaneous measurements
of CDT, GGT, and MCV in patients seen in an emergency department or primary
care center, the sensitivity and specificity of the tests as markers of alcohol
consumption of >60 g a day were 0.58 and 0.82 for CDT, 0.69 and 0.65 for
GGT, and 0.27 and 0.91 for MCV, respectively (29). Using the combination of
CDT and GGT increases sensitivity by 20% above either marker alone, without
compromising specificity (30).
Serum aminotransferases, particularly aspartate amino transferase (AST) and
alanine aminotransferase (ALT), may be elevated in patients with alcohol use
disorder. However, these tests are not as sensitive as markers for alcohol use
disorder as the GGT. AST is usually more elevated than ALT in patients with
alcohol-related liver disease. When ALT is more elevated than AST, alcohol is
less likely to be the cause. Although elevations of the aminotransferases may
suggest alcohol-related liver disease, none of the abnormal liver enzymes can
predict alcohol use disorder or intoxication.
Another alcohol biomarker, phosphatidylethanol (PEth) is a phospholipid in
cellular membranes that is abnormally produced in the presence of alcohol. PEth
testing of blood can be useful to identify heavy alcohol use within the prior 2-3
weeks. A PEth level >8 ng/mL has been used to identify heavy drinking, but
accuracy may be limited and further study is warranted before it is adopted in
widespread clinical use (31,32).
It is important to note that there are a number of potential pitfalls to consider
when using alcohol biomarkers in clinical care. Patients with a low pretest
probability are more likely to have false-positive results. None of the currently
available biomarkers are sufficiently sensitive and specific to be used as
generalized “screening tests” for the spectrum of alcohol use that can affect
health (unhealthy use, from risky use through the alcohol use disorder).
Amphetamines
Amphetamines are a group of stimulants that include amphetamine;
methamphetamine; “Ecstasy” or “Molly,” which is MDMA (3,4-
methylenedioxymethamphetamine) or MDA (3,4-methylenedioxyamphetamine);
and “Eve,” which is MDEA (3,4-methylenedioxy-N-ethylamphetamine).
Amphetamine is a metabolite of methamphetamine. Both amphetamine and
methamphetamine have D- and L-isomers. As the D-isomers of amphetamine and
methamphetamine have stronger central nervous system effects, they are used
more often than the L-isomers. Screening tests for amphetamines are usually
targeted to methamphetamine and can have variable cross-reactivity with
MDMA, MDEA, and MDA. Confirmatory methods (gas chromatography/mass
spectrometry [GC/MS] amphetamine assays) can distinguish methamphetamine
from amphetamine; specialized GC/MS testing and chiral analysis, can
differentiate L-isomers from D-isomers (33). Newer liquid chromatography/mass
spectrometry (LC/MS) methods have also been developed to identify MDMA
and MDA (34,35).
Compared with other commonly tested substances, amphetamines have the
most false-positive screening tests. Many sympathomimetic amines with
structures similar to amphetamines have cross-reactivity with the immunoassays,
causing false-positive results (36). Examples of substances that have been
reported to cause positive results include the decongestants
phenylpropanolamine, pseudoephedrine, and L-methamphetamine (found in the
nasal decongestant used in Vicks nasal inhaler) and appetite suppressants
containing ephedrine and phentermine. Other prescription medications, such as
selegiline or benzphetamine, are metabolized to either amphetamine or
methamphetamine and can also cause positive results. Importantly, several other
medications that are commonly prescribed have been found to cross-react with
amphetamine immunoassays, including fluoxetine, ranitidine, bupropion, and
labetalol. Regarding commonly used stimulant medications for Attention Deficit
Hyperactivity Disorder, Adderall is a mixture of L-amphetamine and D-
amphetamine and will give a positive test for amphetamine, while Ritalin
(methylphenidate) is not metabolized to amphetamine or methamphetamine and
is not detected on confirmatory testing for amphetamine or methamphetamine.
Urine pH influences the excretion of amphetamines. At high pH levels, there
is a marked reduction in amphetamine and methamphetamine excretion.
Individuals have ingested large quantities of bicarbonate to reduce the amount of
amphetamines excreted in the urine. The duration of detection of amphetamine
in the urine by immunoassay is variable but generally accepted to be 1-3 days
(37). With repeating daily use of methamphetamine, detection is up to 3 days in
urine and 1 day in oral fluid after last use (38).
Barbiturates
Barbiturates, which are central nervous system depressants, are divided into
three categories, depending on their duration of action. Thiopental is an ultra–
short-acting barbiturate used in anesthesia. The short-acting barbiturates include
pentobarbital, secobarbital, amobarbital, and butalbital (in combination
preparations to treat headaches). The long-acting barbiturates, such as
phenobarbital, are used therapeutically as anticonvulsants and are rarely
misused. The duration of detection in the urine after barbiturate use is variable
and depends on dose. In general, short-acting barbiturates such as butalbital,
pentobarbital, and secobarbital can be detected from 1 to 4 days after use, while
long-acting barbiturates such as phenobarbital can be detected for several weeks
after use (39). With the exception of phenobarbital, only a small portion of the
parent substance is found in the urine. The amount of cross-reactivity with other
compounds varies with each assay.
Benzodiazepines
The interpretation of urine immunoassays for benzodiazepines is complicated by
the multiple substances available, their variable potencies (allowing a large dose
range), and their diverse metabolites. Urine specimens usually contain little of
the parent benzodiazepine. Many benzodiazepines show poor cross-reactivity
with commonly used immunoassays (12), leading to negative results despite
ingestion. This can be explained by their metabolic pathways. For example,
clorazepate, chlordiazepoxide, and diazepam are metabolized to nordiazepam
and oxazepam. Clonazepam is metabolized to 7-aminoclonazepine (40).
Alprazolam, lorazepam, and triazolam are excreted as glucuronide conjugates,
distinct from oxazepam conjugates. Many of the benzodiazepine immunoassays
are commonly designed to detect nordiazepam or oxazepam. An immunoassay
that is targeted to detect oxazepam is less likely to detect clonazepam,
lorazepam, or triazolam, unless they are present in high doses. Reviewing the
package insert and communicating with the laboratory are important to
understand the sensitivity of the particular assay for different benzodiazepines
and confirmatory testing may be needed.
The cutoff for benzodiazepine immunoassays usually is either 200 or 300
ng/mL, which can detect high doses but may not detect a therapeutic dose. The
high-potency benzodiazepines, such as triazolam, are more difficult to detect in
immunoassays because they are prescribed in low doses. Neither the
benzodiazepine antagonist flumazenil, nor non-benzodiazepine GABA A-
receptor agonist sleep aids such as zolpidem or eszopiclone, are detected on
typical benzodiazepine immunoassays.
Cocaine
Cocaine hydrochloride is the powdered form of cocaine. It is water soluble and
can be inhaled nasally or mixed with water and injected. The alkaloid form of
cocaine, “crack” or freebase, is not water soluble but vaporizes when heated and
can be smoked (41). Screening urine immunoassays measure benzoylecgonine,
the major urinary cocaine metabolite, commonly using a cutoff of 300 ng/mL.
The detection of cocaine in the urine is variable and depends on the amount of
substance ingested. The usual detection time after cocaine use is 2-3 days,
though there are reports of positive urine assays up to 22 days after high-dose
binges (42).
Immunoassays for benzoylecgonine are quite specific; however, false-
positive immunoassays do occur and can be confirmed by a negative GC/MS test
for benzoylecgonine. The ingestion of coca tea has been shown to give positive
urine immunoassays (43). Immunoassays and GC/MS do not differentiate
cocaine hydrochloride from crack cocaine.
Lysergic Acid Diethylamide

The hallucinogen LSD (lysergic acid diethylamide) is extensively metabolized
so that <1% appears unchanged in the urine. The major human metabolite is nor-
LSD (N-desmethyl-LSD). Most standard immunoassay panels do not include
LSD. At a cutoff of 0.5 ng/mL, urine immunoassays detect LSD for 2-5 days
after use (44). One study found a 4% rate of false-positive immunoassays,
occurring in patients using amitriptyline, chlorpromazine, doxepin, fluoxetine,
haloperidol, metoclopramide, risperidone, sertraline, thioridazine, and verapamil
(45).
Marijuana
The primary psychoactive component of the marijuana plant is THC. When
smoked, THC is absorbed quickly into the circulation, with an elimination half-
life estimated to be between 20 and 30 hours. THC has a highly lipophilic nature
and is stored in fat tissues, where it is slowly released back into the circulation.
Most laboratories measure the inactive metabolite 11-nor-Δ9-THC-9-carboxylic
acid (abbreviated THC-COOH or THCA).
Urine screening tests for marijuana typically use cutoffs of 20, 50, or 100
ng/mL. The current federally mandated cutoff for workplace testing is 50 ng/mL.
The detection time for marijuana is variable and depends on the amount
ingested, whether the person is a chronic or an occasional user, and the
sensitivity of the assay. In the 1980s, when assays were less specific for TCH-
COOH, studies reported detection of marijuana in urine for weeks or months
after use. Current research suggests that the detection time is shorter than
previously described (46). The mean detection time of a single marijuana
cigarette is <2 days using a 50 ng/mL cutoff immunoassay (47) and is 3-4 days
using a 15 ng/mL cutoff on GC/MS (48). In frequent users, urine specimens
were found positive for THC-COOH up to 27 days after last use using an
immunoassay with a cutoff of 20 ng/mL (49).
A positive urine THC-COOH test is helpful in identifying past marijuana
use, but it does not correlate with level of impairment. Oral fluids and blood are
being used in some states to help determine if individuals are driving under the
influence of drugs. Oral fluid levels of THC are high after marijuana use but
decline over several hours to low levels. Work is ongoing to determine
appropriate cutoffs for determining impairment, recognizing that levels vary
with different assays (50).
Oral ingestion of hemp seed oil or dronabinol (Marinol), a synthetic THC
used for treatment of chemotherapy-associated nausea and HIV-related anorexia,
can result in positive urine test results for marijuana (51). In the past,
immunoassays gave false-positive results with nonsteroidal anti-inflammatory
drugs such as ibuprofen and naproxen sodium. Current assays have been
modified to eliminate this cross-reactivity. Cannabis products that include
cannabidiol (CBD) or other cannabinoids but do not contain THC are unlikely to
cross-react with marijuana assays, which are designed to detect THC.
Confirmation by GC/MS of a positive screening immunoassay can be done when
there are legal implications.
There has been some debate about the degree to which passive exposure to
marijuana smoke influences screening tests. In experimental studies using
extreme conditions, urine specimens of individuals passively exposed to high
concentrations of marijuana smoke did test positive with immunoassays (52).
However, on quantitative GC/MS, the concentrations of THC-COOH during
more realistic exposure generally are <10 ng/mL, below the cutoffs used in
federal workplace or clinical testing (53).
Opioids
Opiates are derived from opium, the extract of the seeds of the opium poppy, and
include morphine, codeine, and heroin. The term opioid is more comprehensive
and includes all agonists and antagonists with morphine-like activity, including
natural opiates, semisynthetic substances (eg, hydrocodone, hydromorphone,
oxycodone, and oxymorphone), and synthetic substances (eg, methadone,
buprenorphine, meperidine, fentanyl, and tramadol). Notably, poppy seeds
include both morphine and codeine.
The evaluation of the initial opiate screening immunoassay can be confusing.
Many clinicians assume the immunoassays for “opiates” are a reliable screen for
all opioids. Currently available opiate immunoassays are targeted to detect
opiates, using morphine for the target. These opiate immunoassays have little or
no cross-reactivity with synthetic opioids and variable cross-reactivity with
semisynthetic opioids. For example, using such an assay, a patient taking
oxycodone could have a negative urine screen for opiates (12). Because poppy
seeds contain morphine and codeine, ingestion can result in positive urine opiate
screens for 48 hours at a cutoff of 300 ng/mL (54). As a result, in 1997, the
federal government raised the screening cutoff for opiate testing in workplace
programs from 300 to 2000 ng/mL, although many clinical laboratories still use
a cutoff value of 300 ng/mL. In addition, dextromethorphan and the opioid
antagonists naltrexone and naloxone do not cross-react with immunoassays for
opiates (55–57). To determine which opioids show significant cross-reactivity
with opiate immunoassays, one must review the package insert, where the
concentrations of substances that produce positive tests are listed.
To complement these opiate immunoassay tests, immunoassays have been
developed to detect semisynthetic and synthetic opioids such as oxycodone,
methadone, fentanyl, and buprenorphine. At common cutoffs, most detect the
substance in the urine for 2-3 days. New assays have been produced to detect
carfentanil, the extremely potent opioid that has recently been associated with
many overdose deaths. Some screening panels may include certain semisynthetic
and synthetic opioids. This is typically indicated on the test itself, as well as on
the package insert. If screening immunoassays for these substances are not
available, it may be appropriate to skip directly to the confirmatory GC/MS or
LC/MS-MS for the substance in question.
Knowledge of the metabolic pathways of commonly prescribed opioids is
required to accurately interpret opioid screening and confirmatory testing (58)
(see Fig. 23-1). The standard opiate immunoassay is targeted to morphine, so
any compounds that are metabolized to morphine, including codeine and heroin,
are likely to be detectable on a screening opiate test. It is also important to note
that in the process of heroin metabolism, a short-acting metabolite, 6-
monoacetylmorphine (6-MAM), is produced, which then is hydrolyzed to
morphine. The only finding in the urine that unequivocally identifies heroin use
is the detection of 6-MAM. This metabolite is the specific by-product of heroin
metabolism and not a metabolite of morphine, codeine, poppy seeds, or other
synthetic opioids. However, 6-MAM is rapidly eliminated and usually detected
in the urine for <8 hours after heroin use. Although regulations for federal
workplace programs require testing for 6-MAM, it is not routinely included in
clinical testing.
Figure 23-1 Opioid metabolic pathways. Fentanyl,

meperidine, and methadone do not metabolize to morphine,
morphine derivatives, oxycodone, or oxymorphone.
The interpretation of confirmatory testing for specific opioids is also

complicated by the fact that some prescribed opioids are actually minor
metabolites of other opioids (see Table 23-3). For example, hydrocodone is
minor metabolite of codeine (59), oxymorphone is a metabolite of oxycodone
(60,61), and hydromorphone is a metabolite of hydrocodone (62) and morphine
(63,64). For example, GC/MS may detect oxymorphone in a patient who is
prescribed oxycodone, as oxymorphone is a minor metabolite of oxycodone. In
addition, one study found traces of hydrocodone in patients taking large doses of
oxycodone (65). Because hydrocodone is not a metabolite of oxycodone, a
possible explanation is that the oxycodone products were contaminated by traces
of hydrocodone.
Table 23-3
aDepends on the cross-reactivity of the opiate assay with the prescribed medication; varies among assays.
bNegative results may occur due to low or no recent use, causing levels below the cutoff; varies among
assays.
Attention to the metabolism of opioids can be helpful if there is concern that an

individual may be “spiking” a urine specimen (eg, to falsely produce a positive
test result if the patient is diverting it rather than ingesting it). Confirmatory
testing can be done to detect the presence of metabolites created only after
internal metabolism, such as norbuprenorphine from buprenorphine metabolism
and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine from methadone
metabolism (66).
Phencyclidine
Phencyclidine (PCP) in powdered form (“angel dust”) can be inhaled nasally or
smoked, or PCP can be ingested in tablet form. The federal government requires
PCP testing in drug screening programs for federal employees. Laboratories that
are not federally regulated may include PCP in the screen, depending on the
prevalence of PCP use in a given community.
Using a cutoff value of 25 ng/dL, urine immunoassay results are positive for
~7 days after a single dose and for up to 21 days after chronic use. Oral fluid
tests are promising because saliva levels of PCP are higher than blood levels, and
PCP may be more stable in saliva than urine (44).
Lab Testing for Newer Substances

Newer substances, such as synthetic cannabinoids and bath salts, as well as
ketamine, gamma-hydroxybutyrate (GHB), salvia, and flunitrazepam
(Rohypnol) are not typically tested for in routine testing panels. This may
contribute to their popularity for recreational use or in some cases, for their use
in drug-facilitated sexual assault. They are synthetically developed analogues of
more classic drugs like marijuana, amphetamines, and benzodiazepines. While
some commercial laboratories have developed specialized “club drug” test
panels, they are not detected in routine clinical screens.
Synthetic cannabinoids refer to a diverse and expanding group of substances
including aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, naphthoylindoles,
and aryl sulfonamides and are present in herbal products such as “Spice,” “K2,”
and “Kronic.” Synthetic cannabinoids are closely related to the structure of THC
and act as agonists at the cannabinoid receptors. In 2011, the U.S. Drug
Enforcement Agency declared the synthetic compounds illegal but new
compounds continue to be developed (67). These compounds are not detected by
routine screening for marijuana designed to detect THC, but specific
immunoassay tests and confirmatory GC/MS or LC/MS-MS tests are
increasingly available to detect an expanding group of synthetic cannabinoids
and their urinary metabolites (68–70).
Substances called “bath salts” are synthetic stimulants derived from
cathinone, which is naturally found in the khat plant. Most products contain 3,4-
methylenedioxypyrovalerone (MDPV) or mephedrone. These are not detected in
routine clinical screens. GC/MS can detect MDPV in urine if bath salts have
been consumed <20 hours prior to presentation (71).
Ketamine, a noncompetitive NMDA receptor antagonist that blocks
glutamate, is used recreationally and there is an evolving literature and clinical
exploration of ketamine as a rapid antidepressant. Ketamine is metabolized to
norketamine, which is not detected on standard urine toxicology screens.
Commercially available immunoassays can detect ketamine for ~3 days after
use; more sensitive GC/MS can detect for a week or more, depending on the
amount used (72).
GHB acts as a short-acting agonist at GHB and GABA(B) receptors, leading
to CNS depression. It is used recreationally and also has been associated with
sexual assault. GHB can be detected on GC/MS testing but has a window of
detection of <12 hours in urine after a single episode of use and an even shorter
window in plasma. Flunitrazepam (Rohypnol) is a powerful benzodiazepine also
used recreationally and in sexual assault. It can be detected in most urine
immunoassays for benzodiazepines, for up to 12 days (73).
Ethical Considerations
Use of drug testing to monitor patients during treatment for substance use
disorder is a well-established process that is consistently recommended and may
detect the use of substances not reported by patients during the clinical
assessment (74,75). However, clinical guidelines and standard of care regarding
the use of drug testing in other aspects of clinical care, for example, for patients
who are prescribed opioids for chronic pain, are rapidly evolving (76). Drug
testing in that setting provides information about the use of illicit or prescribed
substances that is important for clinicians assessing the safety and use of
prescribed medications. However, as noted throughout this chapter, there are
limitations to drug testing that require careful interpretation within an individual
context. Further, the American Medical Association, American Academy of
Pediatrics, and the U.S. Preventive Services Task Force (USPSTF) recommend
asking about alcohol and substance use when obtaining a patient history, but
none recommends routine laboratory screening for alcohol or other substances in
asymptomatic adults or adolescents in clinical settings.
In clinical practice, testing is commonly ordered under a general “consent to
treatment” when it is ordered as a diagnostic test to guide treatment, without
specific informed consent. However, because of concerns about the technical
limitations of testing, patient autonomy, and potential implications of a positive
test, some favor obtaining informed consent for drug testing (77). The American
Academy of Pediatrics recommends that assent should be obtained from
adolescents for drug testing and sharing results, including with parents (78).
Given the limitations of testing and potential implications, care must be
taken when interpreting results not to draw premature or mistaken conclusions
about substance use that could impact patients clinically, socially, legally, or
financially (74). Further, confidentiality about drug-testing results should be
protected and providers should adhere to current regulations about disclosure of
medical records, such as the Health Insurance Protection and Accountability Act
of 1996 (Pub L No. 104-191), and federal substance use disorder confidentiality
regulations (CFR 42 Part 2), which applies to substance use disorder specialty
settings.
CONCLUSIONS
When performed in an appropriate clinical setting, laboratory testing is a useful
complement to self-report. Laboratory testing can help to identify substance use,
support the diagnosis and treatment of substance use disorders, and monitor for
safety and adherence in patients prescribed controlled substances. However,
clinicians must understand the limitations of any test used. For alcohol, breath
and blood testing can quantitate recent ingestion, but none of the markers for
unhealthy alcohol use are ideal screening tests. For other substances, urine
testing can detect substance use, usually within the preceding few days, but is
insufficient to identify a substance use disorder, which is a clinical diagnosis.
An important consideration is that laboratory testing in the clinical setting is
intended to guide diagnosis and treatment planning and does not follow the
stringent requirements of workplace or forensic testing. The clinician must
integrate findings from the history, including currently-prescribed medications,
and physical exam with findings from laboratory testing for accurate
interpretation and management.
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CHAPTER 24
Assessment
Theodore V. Parran Jr, Mark Bondeson, Richard A.
McCormick, and Christina M. Delos Reyes
CHAPTER OUTLINE
Assessment of Patients With Substance Use
Needs of Different Assessors
Tasks of the Assessment Process
Sources of Assessment Information
Assessment Tools
Summary
ASSESSMENT OF PATIENTS WITH

SUBSTANCE USE
Individualized patient assessment is a basic clinical skill and is one of the
foundations of quality patient care. As such, it is introduced in the earliest levels
of health professional training, and the development of assessment skills is
critically evaluated by health educators. Patient assessment can also be an
extremely complex and sophisticated clinical or research evaluation involving a
multidisciplinary team and multiple forms of patient testing. The importance of
assessment in patient evaluation, treatment planning and evolution of the
treatment plan, patient safety, and provision of optimal patient care cannot be
overstated. Quality assessment bridges the gap between patient diagnosis and the
initiation of treatment, ensuring the accuracy of the initial diagnosis and
identifying the most effective and efficient care. Patient assessment is as
important when dealing with substance use disorders as it is for other medical or
psychiatric illnesses.
Addiction affects the behavioral control areas in the brain. As a
consequence, signs and symptoms of the disease of addiction are primarily
displayed in terms of aberrant, problematic, and atypical behaviors. Contrary to
most other diseases, the morbidity of this disease often involves the intrapersonal
sense of self (self-image, self-respect, self-concept, sense of self-efficacy, and
even psychiatric symptomatology are often the earliest evidence of disease),
interpersonal relationships (family and close friends and then social relationships
suffer), avocations and hobbies, financial status, legal standing, employment or
school performance, and to physical or end-organ damage. Addiction typically
affects all of these varied domains of life and is affected in turn by many
domains, including legal and licensure status, insurance eligibility, comorbid
medical and psychiatric conditions, and family relationships (CSAT TIP #27)
(1). This is why the assessment process is such a critical aspect of the approach
to the disease of addiction (2).
NEEDS OF DIFFERENT ASSESSORS

Different clinicians have different clinical decision-making needs when it comes
to the initial assessment of substance use disorders, and these different clinicians
can be generally divided into four groups: primary care clinicians, addiction
medicine or psychiatry specialists, substance use disorder treatment programs,
and substance use disorder researchers. The use of different levels of assessment
is patient-centered as it provides the patient with the right degree of assessment
necessary for shared decision-making between clinician and patient. It also
provides more highly individualized clinical decision-making wherever the
patient may access help (enhancing use of the “no wrong door” approach).
Across these settings, assessment is a necessary part of the evaluation of patients
with addiction and is a critical bridge between screening and diagnosis and
treatment planning. There are many tools available to assist in the assessment
process. Choosing the right tool for the clinical needs of the patient and the
capability of the clinician or treatment program can be difficult. Staff training
and competencies and the availability of time and assessment resources (eg,
computerized database access) can all impact on the selection of assessment
tools.
Primary Care Assessment Needs and Tools

The primary care provider (PCP) needs to perform a reasonably brief patient
assessment to quickly verify the diagnosis, gauge the severity of the disease
from the perspective of psychosocial morbidity/end-organ damage/physical
dependence, gauge the patient’s readiness for behavior change, and screen for
immediately important medical or psychiatric comorbidities, to include level of
suicide risk. This needs to be done in parts of one or more office visits through
patient interview, physical examination, use of one or more validated
questionnaires or assessment tools, laboratory including toxicology, query of the
Prescription Drug Monitoring Program (PDMP) database, and, if possible,
corroboration in person or by phone from collateral sources (family, friends,
other healthcare providers) after informed consent and release of information for
matters related to substance use disorder. As is the case for other medical
illnesses, different PCPs may have different levels of expertise and involvement
in the assessment and management of addiction. For example, some PCPs may
choose more minimal involvement, which would include the ability to identify
the substance use disorder, the primary substance, severity of substance use
disorder, impact on functional abilities, and readiness to change. Others may
want to be more closely involved with management or even deliver treatment
(eg, buprenorphine) and coordinate specialty counseling referrals themselves. In
that circumstance, more detailed and specific assessments would be necessary.
The PCP should utilize a structured approach to this assessment as much as
possible to try to ensure an appropriately careful and thorough evaluation. The
assessment resources available to the PCP are limited but quite adequate to
perform an addiction assessment. The provider can use and follow-up on the
results of typically used screening tools like the single screening questions,
Alcohol Use Disorders Identification Test—consumption items—(AUDIT-C),
AUDIT, and Drug Abuse Screening Test (DAST) by eliciting information about
patterns of use, past attempts at controlling use, adverse consequences of use,
possible physiological dependence, and quantity/frequency of data (included in
some screening instruments such as the AUDIT or Alcohol Smoking and
Substance Involvement Screening Test [ASSIST]). Screening question responses
already provide substantial information and can even be used directly. For
example, an AUDIT-C score of 7 or greater substantially increases the
probability of pre–DSM5-defined alcohol dependence; the frequency of use
reported on single-item screeners, AUDIT and AUDIT-C, is likely correlated
with severity. And longer questionnaires (eg, ASSIST) and screening tests
recommended decades ago but no longer recommended for screening because
they focus only on more severe and lifetime disorders (eg, CAGE/CAGE-AID,
family-CAGE [F-CAGE]) can be useful as brief assessments. This strategy helps
with assessing psychosocial morbidity, risk of withdrawal, and need for
withdrawal management and suggests whether or not specialized treatments (eg,
behavioral therapies or pharmacotherapies, some of which can be prescribed by
PCPs) might be indicated. Another way to assess for severity is to interview the
patient regarding the DSM-5 criteria to determine their presence or absence. In
addition, the primary care physician would want to inquire about prior success or
failure with abstinence, attempts at controlled use (harm reduction concepts),
prior treatment experience, and affiliation with the 12-step or mutual/self-help
community. Any primary care assessment should include laboratory evaluation
including toxicology testing, complete blood count, and liver profile and the use
of the pharmacy board website or PDMP database (now available in all but one
state in the United States). Assessments should be repeated over time to identify
treatment response and needs for changes in strategy. Because of this,
assessments that both provide useful information and might be responsive to
time and even the target of treatment are particularly useful (eg, number of
heavy drinking days). Brief depression and anxiety screening are always
important, as are a medical history review and review of systems to identify
illnesses and symptoms that may be related to substance use. Brief tools can also
be used to assess readiness to change. For example, the clinician can ask how
ready the patient is to make a change, how important it is to the patients to
change, and how confident the patients are that they could change, each on a
scale from 0 to 10. The answers can be used to generate discussion toward
change (eg, “why did you say four and not a zero?”).
Many patients presenting to a PCP may not meet criteria for a substance use
disorder, but may be using alcohol or other substances at a level that is harmful
and hazardous to their health and well-being. The AUDIT and AUDIT-C, and
other screening tools, can be utilized to identify these risks, using a lower cutoff
score as is recommended to screen for unhealthy use. Questioning should also
focus on bingeing and serious risky behaviors such as driving while under the
influence. Hazardous alcohol and drug use is also often a precursor to more
serious substance use and often is the most easily recognizable symptom in a
more complex array of problems that can include suicidality, anger control,
domestic abuse, and mental disorders such as posttraumatic stress disorder
(PTSD).
The development and deployment of evidence-based approaches for
technology-assisted care of patients with substance use disorders are growing
and will offer increasing opportunities for enhancing assessment, referral, and
treatment. They offer specific advantages to PCPs, who must maximize the
efficiency of the assessment and referral process. Standardized assessment tools
can be self-administered on a variety of platforms including websites, app for
smartphones, and computer tablets provided in waiting rooms. These
applications can, ideally, be linked to the electronic health record (EHR), making
the results of the evaluation immediately available to the provider and permitting
the trending of scores over time. Increasingly, it is becoming possible to have the
patient self-administer assessments at home utilizing the EHR’s patient portal.
This can be done prior to an appointment or on a regular basis between
appointments. Settings with high levels of EHR integration have successfully
implemented such programs.
Technology also offers options that the PCP can use to either provide brief
interventions in the office or can recommend that appropriate patients access
directly (3). Examples would include a decision support algorithm linked to the
EHR in the Veterans Health System that guides the PCP in providing very brief
feedback and assistance and app and Web programs such as Drinker’s Check-up
(4). This Check-up begins with a short assessment (AUDIT) and then a
motivationally driven presentation of feedback and options for change tailored to
the patient’s assessed level of need. Emerging research indicates that Web- or
app-based interventions are well accepted and often an effective option for some
patients, particularly those at the hazardous stage of use.
Addiction Specialist Assessment Needs and

Tools
The addiction medicine or psychiatry specialist will approach the assessment
from a different perspective. Certainly, assessing for addiction and stage of
readiness for behavior change, as well as expert evaluation for medical
withdrawal or withdrawal management needs, must be accomplished. Further
evaluation for co-occurring psychiatric disorders, a more thorough family
assessment, impact on functional status, careful evaluation of all prior
assessments and attempts at treatment, patterns of substantial remissions and
relapses, and the potential role for pharmacotherapy should all be part of this
specialist assessment.
The addiction medicine or psychiatry physician’s needs, when approaching
the assessment process, require much more in-depth evaluation and typically
necessitate the use of more formal tools for staging the disease and quantifying
disease severity. The use of the aforementioned screening and brief assessment
tools and a more extensive diagnostic interview is required. In addition, formal
depression and anxiety screening with tools, such as the Beck Depression
Inventory or the Hamilton Anxiety Scale, is often performed. In addition,
assessing for new emergence of or change in symptoms of other psychiatric
disorders should be performed. A thorough review of prior treatments, length
and characteristics of remissions, patterns and triggers for relapse, and current
supports and resources available for treatment is essential. Assessment of the
readiness for behavior change, of the level of commitment to a recovery
program, and of the possibilities for pharmacotherapy is necessary as is careful
evaluation for acute, subacute, and postacute withdrawal issues. Interviewing
significant others about the patient in order to corroborate the history is even
more essential, but still requires informed consent and a release of information
for addiction-related information.
Substance Use Disorder Treatment Provider

Needs and Tools
The substance use disorder treatment program generally has the time and
resources to place more emphasis on prior treatment experiences, identification
and management of co-occurring medical and psychiatric conditions, family
issues and the therapeutic milieu of the living environment, and past relapse
patterns (see Chapter 30). The purpose of assessment in this setting extends to
details relevant to designing individualized treatment approaches.
The addiction treatment program must use a formalized addiction assessment
process for quality control and accreditation reasons. A full medical history and
physical exam are mandatory focusing on the aforementioned areas, but a
structured interview such as the addiction severity index (ASI) or even the
Substance-Related and Addictive Disorders module of the Structured Clinical
Interview for DSM-5 (SCID-5), the Mini-International Neuropsychiatric
Interview (MINI) (5), or the Composite International Diagnostic Interview
Substance Abuse Module (CIDI-SAM) should also be used. The SCID and the
MINI have been updated to DSM-5. Programs that care for patients with a high
prevalence of co-occurring psychiatric disorders will utilize the more extensive
SCID or at least will need to use specific anxiety and depression screens.
Assessing treatment readiness and treatment resistance, as well as relapse
patterns and coping skills, is typically a part of the addiction treatment program
assessment process. Corroboration of this assessment process is absolutely
necessary.
Substance Use Disorder Researcher Needs

The substance use disorder research or evaluation organization has a very
different goal when it comes to assessment. The focus tends to be on quantitative
evaluation of the degree of accumulated morbidity in the patient’s life, patient-
centered research into treatment-matching efforts, identification and exploration
of patient characteristics that predict response to treatment, and the elucidation
of different types and subtypes of addiction disorders. Well-validated diagnostic
tools and measures of change over time, administered in ways that minimize
error, are key.
TASKS OF THE ASSESSMENT PROCESS
Assessment of substance use disorders within the context of the rest of the
patient’s life circumstances is a process that should be utilized when evaluating
every patient. The nature of the assessment process is influenced not only by
patient factors but also by clinician and organizational factors. Therefore, the
tools used in an assessment may change depending upon the clinical situation,
the competency of and resources available to the clinician, and the specific
characteristics of patient presentation, but the basic areas to be assessed remain
fairly constant as indicated in Table 24-1.
TABLE 24-1 Major Areas for Addiction Assessment
Generally speaking, assessment of a substance use disorder is utilized for one or

more of the following tasks: diagnostic verification, assessing for physiological
dependence and the potential need for stabilization and medical withdrawal
management, staging disease severity, identifying the domains of life affected by
the disease, evaluating for additional medical or psychiatric diagnosis,
quantifying the disease-associated morbidity, identifying characteristics of the
disease that are important from a prognostic or possibly from a treatment-
matching perspective, quantifying the impact of treatment on disease-associated
morbidity, or attempting to determine subtypes of addiction.
The assessment process can also be thought about from the perspective of
timing. Since 1990, the addiction treatment field has been challenged to improve
the pretreatment assessment of alcohol and other addiction in order to provide
better treatment decisions (6). More recently, the concept of intratreatment and
even posttreatment assessment has gained favor, urging formal ongoing
assessment performed at transition points in the treatment process. This permits
the continued adaptation of the treatment plan, a key criterion for most treatment
program accreditation reviews and for good care like the care of any other illness
over time (5,7). Pretreatment assessments are focused on identifying the
treatment needs of the patient, identifying positive and negative predictive
factors for treatment retention, quantifying the pretreatment level of morbidity
and impairment of functioning, and screening for urgent co-occurring medical,
psychiatric, and psychosocial issues. It is critical that “pretreatment” assessment
not be a barrier to treatment entry (eg, requirements for hours and hours of
assessment before committing to or proceeding with help for the patient).
Intratreatment assessment updates should be performed at periodic intervals
during the formal treatment phase, especially at times of treatment transition or
whenever substantial additional or new clinical information becomes available.
This intratreatment assessment update should focus on organizing the
accumulating data from the treatment experience in such a way as to inform the
ongoing treatment planning and patient diagnostic process. This concept, also
known as “measurement-based care,” is the norm for much of health care (one
initiates treatment for hypertension or depression and then assesses response by
measuring blood pressure levels and symptoms to determine if treatment is
adequate or needs change). Assessments must be used this way in the treatment
of addiction; they are only useful to the extent their results are used in treatment
decisions. Posttreatment assessment is a bit of a misnomer since the concept that
for all with addiction have a start and end date for treatment is antiquated and,
again, a foreign concept to the management of chronic illness for other health
conditions (eg, there is no “posttreatment” period for hypertension).
Nonetheless, because of the way the addiction treatment system is largely
organized around discrete treatment programs and discrete episodes (as opposed
to patient illness characteristics and needs), many patients continue to experience
discrete episodes of specialized treatment. Assessment at the conclusion of such
episodes or differing levels of care could be called “posttreatment”—an
assessment update performed at the end of that level of care to summarize the
treatment experience, inform follow-up monitoring, focus on relapse prevention,
reorder the problem list, and focus attention on additional, new, or previously
deferred problems. In addition, posttreatment assessment can be used to quantify
the patient’s posttreatment level of morbidity and impairment of functioning.
The difference between pretreatment and posttreatment assessment can,
therefore, quantify and characterize the difference in patient morbidity and thus
measure the impact of addiction treatment. “Posttreatment” assessments are now
beginning to be recurrent and longitudinal as part of continuing care (that may
occur across “program” boundaries according to patient need).
SOURCES OF ASSESSMENT
INFORMATION
As domains of patient life affected by addiction include such varied areas as
intrapersonal, interpersonal, avocations and hobbies, financial status, legal
issues, employment or school performance, and physical or end-organ damage, it
becomes incumbent on the assessment process to gather information from many
different—and at times atypical—sources. This is in contrast to the assessment
of most medical or surgical conditions wherein the usual and adequate sources
for assessment and management are provided by the initial history and physical
followed by laboratory and diagnostic study review.
Sources that commonly are utilized in assessing the disease of addiction
include patient history, physical exam, and laboratory results; toxicology testing;
family interview; use of pharmacology (licit and illicit) with special emphasis on
the controlled drug use history; legal history questioning, PDMP data, and
educational and occupational interview; and readiness for behavior change
evaluation. These areas of questioning and examination are even more important
than during routine medical care. Substance use disorders are some of the most
highly stigmatized disorders in our society. As a result, issues of the reliability of
patient self-report are even more suspect than with other health problems faced
by clinicians. It is important to interview patients in ways that minimize
shaming, which might well result in a defensive response style, thus limiting
reliable data gathering. Just as in the area of screening and brief intervention,
patient self-report reliability can be improved by using a consistent series of
questions that progress from general and open-ended to specific information
sought in a more closed-ended question form and by utilizing the family or
significant other interview whenever possible. Additionally, there is some
evidence to suggest patients may be more forthcoming with a self-report tool,
including one administered by electronic means, rather than a face-to-face
interview.
Owing to high rates of psychiatric symptomatology, a psychiatric screening
interview, to include a suicide risk assessment and a violence/homicide risk
assessment, is required. Due to the high rates of interpersonal violence in
patients with substance use disorders, either as a child or as an adult, or both,
assessment for physical emotional or sexual abuse history is critical. Cultural
background, spiritual inclination, and belief system that the patient holds
regarding substance use disorders are critical areas of assessment. As a
consequence, assessment entails extensive patient interview, family interview,
checking pharmacy profiles, toxicology testing, documenting legal issues and
the actual causes of legal issues, and careful review of prior treatment and
relapse experiences. Thus, the assessment process typically is extended in time
and multidisciplinary in nature.
ASSESSMENT TOOLS
A thorough assessment should evaluate each area or domain of patient function
that is necessary for the needs of the clinician performing or requesting the
assessment. As indicated above, typically, the natural history of addiction
involves progressive dysfunction and disability in the major life domains in a
cascade pattern, often starting with the intrapersonal, advancing to the
interpersonal, and eventually progressing to the physical in the later stages. This
is why assessment strategies must be sensitive to the natural history of the
disease of addiction. In addition, the assessment tool used should be reliable,
reproducible, and verifiable. Diagnostic and assessment strategies are often
evaluated based upon their convergent validity (consistency with an established
best practice of “gold standard”) and ability to predict different outcomes
(predictive validity). A high-quality assessment tool should also have face
validity (seems to be clear and logical and makes sense), as well as retest and
interrater reliability (reoffering the assessment to the same patient by the same or
a different staff member should produce a consistent result).
This section suggests tools to assist the clinician in key assessments. The
clinician often begins by assessing the severity of the patient’s substance use and
for a disorder. There are a number of options that vary in the effort required and
the range of use they span. The instruments highlighted have been shown to be
reliable and valid for the purposes suggested. Some of the tools (like the single
screening questions, AUDIT-C, AUDIT, and DAST) are primarily screening
tools, but the assessment process is a clear and direct extension of the screening
and diagnosis process. As a consequence, extending the use of a screening tool
by asking straightforward follow-up questions for each positive screening
response can result in a substantial assessment without needing to use additional
clinical tools. Table 24-2 demonstrates this process of extending a screening tool
for use in assessment. Further information on many of these tools, and other
assessment options, can be found online at niaaa.nih.gov/publications,
drugabuse.gov, or samsha.gov.
TABLE 24-2 Moving from Screening Tools to Patient

Assessment
Screening Tool Results Can Provide
Assessment Information
Screening tool results can be used as a bridge to the assessment process. The
primary way this happens is to use the positive responses for follow-up
questions. The process of clarifying positive responses both establishes whether
a positive response is a “true positive” and explores the data behind the positive
response. This establishing “true positives” and following up for functional data
that underlies the positive response facilitates the transition from screening to
assessment. For example, asking follow-up questions to the AUDIT-C–positive
responses can give valuable information about the quantity and frequency of use,
patterns of use, efforts to control use, and adverse consequences of use.
A second way to use screening test results to start the assessment process is
to use the screening test “score” to begin a rough estimate of the severity of the
disease. For example, the AUDIT-C can indicate low-risk use, risky use, or
DSM-IV–defined substance dependence depending on the score (2,8–11). An
AUDIT of 15 or greater and an AUDIT-C of 7 or greater substantially increase
the risk of a DSM-IV–defined substance dependence. Similarly, a score of 27 or
greater on the ASSIST or above 12 on the DAST indicates more advanced
disease (12–16). Even single-item screening tools can provide this information
with the past year frequency of drug use (3 or more times) or heavy drinking (8
or more times) being associated with DSM-IV dependence (17).
Some formerly used tools for screening are probably better suited for disease
staging or the assessment process. One of these is the CAGE questionnaire,
where a score of two or more is suggestive of a lifetime diagnosis of substance
use disorder (18). The F-CAGE is also a very useful tool to obtain assessment
data from friends or family members of people with substance use disorders
(19). Additional tools that can be used in this way are the Short Michigan
Alcoholism Screening Test (20) and the CAGE-AID, which is the CAGE
questionnaire adapted to assess for other drug use (21). Realize, however, that
while screening tools may be adapted for use as an aid in assessment and
diagnosis, they are not endorsed by the DSM-5 as a substitute for the gold
standard—a diagnostic interview and examination performed by a clinician
trained in addiction-related disorders.
Diagnostic Assessment Tools

Semistructured clinical interviews designed for administration by trained
evaluators are considered the “gold standard” for establishing reliable diagnoses
of substance use disorders. The Substance-Related and Addictive Disorders
module of the SCID-5 (22,23) utilizes questions paralleling the DSM-5
diagnostic criteria and establishes lifetime and current disorder diagnoses for
alcohol and each psychoactive substance included in DSM-5. Age of onset and
an estimate of current severity are also obtained. The Substance Abuse Module
of the Composite International Diagnostic Interview (CIDI-SAM) (24), a
detailed interview designed to ascertain specific diagnoses of DSM-IV substance
abuse and dependence, is also frequently utilized; updates for DSM-5 are
anticipated. Alternatively, the diagnostic portion of the Substance Abuse
Outcomes Module has been shown to correlate well with the CIDI-SAM, has the
advantage of being considerably shorter to administer than the CIDI-SAM and
can be self-administered, and is designed to be implemented in routine clinical
practice. Alternatively, the MINI can be used. It has been validated in both the
United States and Europe as an alternative to the SCID and the CIDI that is
shorter in administration.
Intoxication and Withdrawal Assessment

Intoxication
Both the patient history and the results of toxicology testing are essential in the
assessment of intoxication and withdrawal. Toxicology testing can be used to
verify recent use, involvement of more than one substance, and current levels of
intoxication. High levels found on toxicology testing, with a relative absence of
obvious physical impairment, are a strong indicator of high levels of tolerance
and of physical dependence.
Often, the first step in conducting an addiction assessment is to establish
degree of risk associated with withdrawal. Once the diagnosis of withdrawal is
made, its risk or severity should be assessed. The Clinical Institute Withdrawal
Assessment for Alcohol, revised (CIWA-Ar) (25), is a brief 10-item scale that
can be administered in <3 minutes. It quantifies the severity of the alcohol
withdrawal syndrome by rating 10 common alcohol withdrawal symptoms and
can be clinically useful in monitoring progress over time. The CIWA has been
adjusted for assessment of benzodiazepine withdrawal, and the Clinical Institute
Narcotic Assessment (CINA) Scale and Clinical Opiate Withdrawal Scale
(COWS) have been developed to quantify opioid withdrawal symptoms as well.
CIWA and CINA scores below 8 indicate mild withdrawal, and scores above 20
indicate severe withdrawal. COWS scores below 12 are considered mild opioid
withdrawal and above 36 are severe withdrawal.
Assessment Tools for Comorbid Conditions

and Functioning
As highlighted earlier, patients with substance use disorders often present with
co-occurring psychiatric disorders that require concomitant or sequential
treatment. The full SCID has modules for each of the other major syndrome
groups, anxiety disorders, affective disorders, and psychotic disorders, as well as
other comorbidities that are common in people with substance use disorders,
most notably the other disorders of impulse control, such as eating disorders and
pathological gambling, and the personality disorders. Each module may stand
alone for the assessment of a particular diagnostic syndrome. Administration of
the full SCID can take 2 hours or more depending on the complexity of the
patient’s presenting problems. The CIDI or the MINI can be shorter alternatives.
Short self-report instruments are available to measure some of the most
common comorbidities. The 18-item Brief Symptom Index (BSI) (26) assesses
psychological distress severity and includes scales for somatization, depression,
and anxiety. It has been shown to be a powerful predictor of poor treatment
outcome among people with substance use disorders (27).
The PHQ-9 (28) assesses symptoms of depression and is highly correlated
with more comprehensive assessments of current major depressive disorder.
Importantly, it includes one question assessing suicidal ideation: “Have you
thought that you would be better off dead or that you wanted to hurt yourself in
some way?” The Beck Depression Inventory (29) and the Beck Anxiety
Inventory are both relatively short (21-item) instruments that take about 10
minutes to administer and can be readministered over time to monitor progress.
Special versions for children (ages 7-14) are also available.
Gambling disorder can be effectively screened for and assessed using the
South Oaks Gambling Screen (SOGS) (30), a short self-report instrument that
has been demonstrated to reliably identify people with problem or DSM-IV–
defined pathological gambling.
As noted, substance use disorders and risky use have broad impact on the
physical and psychosocial functioning of the patient. The ASI provides a reliable
measure of lifetime use and use within the past 30 days for a full range of
commonly used substances (31). It also assesses additional key dimensions of
functioning: medical status; vocational; legal; family, including family history,
and social issues; and psychiatric status. For each dimension, the ASI yields both
composite scores, which are mathematically calculated based on selected
quantifiable items, and a rater-generated severity score. The scores are based on
structured interviews, which take ~1 hour to administer. The ASI sections can be
readministered to assess progress over time. More recently, modifications of the
ASI have been introduced and tailored to the needs of women (32) and teenagers
(33).
Self-report instruments that are available also provide a broadened
assessment of the consequences of use. The Drinker Inventory of Consequences
(DrInc) (34) measures the adverse consequences of alcohol use in five domains:
physical, social, impulsive, interpersonal, and intrapersonal. The 50-item test
takes only about 10 minutes, yielding lifetime and last 3-month scores for each
domain and an overall score. The DrInc has been used widely in clinical trials,
including in a repeated measures design. A companion instrument, the Inventory
of Drug Use Consequences (InDUC) (35), provides similar information for a
broader population of patients using drugs or drugs and alcohol. Finally, the SIP-
AD (short inventory of problems—alcohol and drugs) is a brief 15-item self-
report test that measures physical, social, intrapersonal, impulsive, and
interpersonal consequences of alcohol and drug consumption. Versions of the
SIP exist for alcohol only, drug only, or both.
It is important to assess the motivational level of the patient for engaging in
treatment. Self-report instruments are available, including the Stages of Change
Readiness and Treatment Eagerness Scale (SOCRATES) (36). The 19-item short
form of the self-report instrument assesses motivation to change drinking
behavior. A personal drug use version is also available. Based on the
transtheoretical model of change, it assesses the patient’s level of recognition of
a problem, ambivalence, or uncertainty about changing and whether the patient
is taking steps to change. It has been employed to monitor motivational level and
predict compliance with and outcome of treatment. A similar instrument, the
University of Rhode Island Change Assessment (URICA) (37), is slightly longer
(32 items) and can readily be modified to assess motivation for change across a
range of behaviors, including alcohol, other drugs, or concomitant unhealthy
behaviors. Both instruments are easy to administer and have been used
successfully with a wide range of patients, including patients with severe, co-
occurring psychiatric disorders (38).
When a more comprehensive assessment of resistance to treatment is
needed, most often in the context of a specialized treatment program, the
Recovery Attitude and Treatment Evaluator (RAATE) (39) provides both a 35-
item semistructured clinical interview option (RAATE-CE) (40) and a 94-item
self-report version (RAATE-QI) (40). They both measure five constructs:
resistance to initial treatment, resistance to continuing care, severity of
biomedical problems, severity of psychiatric/psychological problems, and
social/environmental support for recovery. The RAATE-CE is designed for
administration by someone with adequate substance use disorder expertise to
make the ratings required. The QI version provides a more direct patient
perspective on the constructs. Both take ~30 minutes to complete.
Assessment instruments can be valuable aids in constructing a relapse
prevention plan. The patient’s knowledge of the situations that trigger the use of
substances is an important element in any relapse prevention plan. The Inventory
of Drinking Situations (41) is a 100-item self-report instrument that allows a
patient to assess his or her tendency to drink in a variety of situations that can be
categorized as urges and temptations, personal control, unpleasant emotions,
pleasant emotions, conflict, social pressure, physical discomfort, and pleasant
times with others.
In helping the patient prepare a relapse prevention plan, it is also useful to
understand the coping skills that the patient possesses. A number of instruments
are available to assess coping repertoire. The Coping Response Inventory (CRI)
(42) is a relatively short (48-item) self-report instrument that assesses four types
of avoidant coping (emotional discharge, cognitive avoidance, seeking
alternative rewards, resigned acceptance) and four types of approach coping
(logical analysis, problem solving, seeking guidance and support, positive
reappraisal). A youth version is also available.
Although there is ample evidence that treatment can work, adherence to
treatment remains a major impediment to recovery. Self-efficacy and
expectations about the effect of alcohol and drugs have been demonstrated to be
related to adherence across a broad range of disorders. Self-efficacy for alcohol-
related situations can be measured using the Situational Confidence
Questionnaire (SCQ) (43), a 39-item self-report instrument that asks patients to
imagine themselves in a variety of situations and rate their confidence that they
can resist the urge to drink in these situations. It takes ~15 minutes to complete.
A companion instrument, the Drug Taking Confidence Questionnaire (44),
assesses self-efficacy for drug-related situations. Expectations about the effect of
alcohol or drugs can also influence adherence. Specific instruments exist to
measure expectations (eg, the Adult Alcohol Expectancy Questionnaire (45)). A
shorter, 8-item version of the brief SCQ is also available and has been shown to
be comparable to the original version (46).
In summary, there are many assessment tools to choose from, and the choice
of tool will depend largely upon time constraints, the setting in which the
assessment takes place, the credentials and experience of the assessor, and the
intended goal of the assessment. Additionally, state guidelines for agency
certification and national accreditation standards may further dictate the exact
elements that need to appear in an assessment. Agencies and treatment programs
will need to incorporate these elements in order to meet these standards.
Assessment instruments are useful for screening for disorders, determining
diagnosis and severity, and developing treatment plans—they can be used to add
depth and externally validated data to the assessment process so as to
individualize high-quality care. Importantly, the assessment process should never
delay or be a barrier to starting treatment.
Given the inevitable constraints of time facing a clinician, particularly in a
primary care venue, it is often necessary to prioritize the domains assessed and
assessment instruments utilized. Unless the information is already known and
documented, assessing the severity and frequency of use of multiple substances
is a high priority. Often, the client’s level of motivation for change is also a high
priority, since this assessment can determine the next logical step in the
treatment or referral process. Thus, for example, if a patient seen in a primary
care setting is clearly using at levels that are at least hazardous, but indicates no
interest in changing use levels, the clinician may choose to work on increasing
motivation. In order to do so, the clinician may choose to conduct other
assessments that focus on the negative impacts of use on health, vocational life,
or social adjustment. These data can then be utilized to impact the patient’s
decisional balance regarding the pros and cons of continued substance use.
Conversely, for a highly motivated patient, instruments that are designed to
assess situations that lead to use, and coping skills that will help to reduce use,
may be an immediate high priority. Co-occurring mental health conditions are
also a high priority, since they should influence the type of therapies offered as
well as the level of care within which they will be coordinated. As with many of
the domains of assessment highlighted above, comorbidities can first be
screened for with relatively brief self-report instruments, and then those who
screen positive can be further assessed with more comprehensive instruments.
Advances in technology should continue to make it more feasible to conduct
assessments in the primary care setting in a way that does not further impinge on
clinician time and can make the results readily available in the EHR at the time
of the appointment.
An assessment is just the beginning step of the treatment process and is used
to inform effective treatment strategies for the management of substance use
disorders. The assessment process also promotes early engagement and longer-
term retention in treatment. As a general rule, a thorough assessment can usually
be completed in 1-2 hours. The ASAM Patient Placement Criteria provide
further guidance on how to match assessment results to the appropriate level of
care. Ironically, despite the best efforts at assessment and the appropriate
recommendation to a particular level of care, many individuals cannot access all
levels of care, and many communities lack the resources to fund and sustain all
levels of care. For example, if the assessment reveals a diagnosis of severe
opioid use disorder and the Patient Placement Criteria recommend methadone
maintenance, but the local community lacks a methadone clinic, there is not an
alignment between the assessment results and the available resources in the
community. This is the “art” of creating a workable treatment plan and also an
ongoing call to action to advocate for adequate funding of treatment and
“treatment on demand.”
SUMMARY
The assessment process helps to guide healthcare providers who care for patients
with substance use disorders along the care management pathways that are most
strongly supported by evidence. High-quality assessment bridges the gap
between patient screening and diagnosis and the initiation of treatment, ensuring
the accuracy of the initial diagnosis and identifying patient treatment needs from
the perspective of effectiveness and efficiency. Assessment of quality permits the
development of a comprehensive problem list and a thorough treatment plan.
Assessment of all of the various domains of life affected by the disease of
addiction as well as co-occurring medical and psychiatric disorders, withdrawal
management needs, prior treatment, relapse patterns, readiness for change, and
treatment resistance are all critical areas of focus. Finally, some assessment tools
can quantify the impact of addiction on patient’s lives and measure the level of
morbidity and the residual level of functioning. Repeating the use of these
quantitative tools can measure improved functioning and decreased morbidity as
well as help to continue to inform the ongoing process of treatment planning
(6,7,31,35,47,48).
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SUGGESTED READING
Dupont R. New Paradigm for Substance Abuse Treatment. Alcohol, Drugs Healthcare & Treatment.
February 3, 2012. http://www.drugfree.org/join-together/alcohol/a-new-paradigm-for-substance-
abuse-treatment
CHAPTER 25
Environmental Approaches to
Prevention: Communities and Contexts
Paul J. Gruenewald, Joel W. Grube, Robert F. Saltz and
Mallie J. Paschall
CHAPTER OUTLINE
Introduction
Scope of the Problem
Environmental Versus Individual Approaches to Prevention
Domains of Environmental Prevention
Nine Efficacy Trials
Multicomponent Environmental Approaches Considered
The Emergence of Ecologic Research
The Logic of Environmental Prevention
Environmental Prevention and the Role of the Medical Professionals
Glossary
INTRODUCTION
At the conclusion of prohibition in 1933, the 21st amendment to the United
States Constitution broadly delegated control over production and sales of
alcoholic beverages to the states, territories, and possessions: “The transportation
or importation into any State, Territory, or Possession of the United States for
delivery or use therein of intoxicating liquors, in violation of the laws thereof, is
hereby prohibited” (US Constitution, Amend. XXI, Sec. 2). Among many other
options, states have the power to license or monopolize alcohol production,
wholesale distribution, and retail sales; restrict use to certain social contexts or
proscribe use by some groups; limit production of certain beverages or prohibit
sales by beverage type (beer, wine, or spirits); exclude sales on specific days or
times (eg, Sunday or late evening hours); restrict sales to certain types of outlets
(eg, restaurants); and prohibit young people from purchasing or using alcohol.
States establish the regulatory conditions under which alcohol can be sold and so
determine, in large part, the social, economic, physical, and legal environments
for use. Thus, the grand experiment of prohibition was followed by another less
grand but perhaps more important experiment: the progressive liberalization of
alcohol sales by states in the United States. Over the past 85 years, states
progressively deregulated sales, allowed use in more contexts, lowered beverage
taxes and prices, increased numbers of outlets, and, with the exception of the
minimum legal drinking age, lowered legal restrictions on use. As a
consequence, illegal production and distribution have been essentially
eliminated, but this deregulation has led to an increase in many public health
problems (1–3). With the creation of large and profitable alcohol markets,
continued deregulation is actively pursued as a goal by the alcohol beverage and
social hosting industries (4), including aggressive efforts to expand the times and
places in which alcohol can be sold and consumed.
Although state laws and regulations affect the environments in which
alcohol can be sold and used, the impacts of deregulation are felt almost
exclusively at local community and neighborhood levels. A state regulation that
allows special use permits will enable “summer wine festivals” to open across
the state. State alcohol taxes do not keep pace with inflation, so the real price for
a beer at the corner store is reduced every year. Restrictions on numbers of
outlets may limit their numbers in a county overall, but allow overconcentration
in some neighborhoods. Legal consequences of sales to minors may be
substantial but not enforced by local police. For these reasons, many
communities want to push back against deregulation and use community
resources to decrease neighborhood consequences of alcohol use. It is at the
community level that, from a practical perspective, physicians can act to reduce
the impacts of expanding environments for the use of alcohol and other addictive
or psychoactive substances (now including legalized or decriminalized
recreational marijuana and cannabis used as medicine—also known as “medical”
marijuana). With a focus upon the impacts of secondhand smoke on nonsmokers,
young adults, and infants, important gains have been made in reducing or
restricting environments in which tobacco use is possible (5). Similar gains can
be made with regard to alcohol and other drugs. Communities can take control of
many aspects of drug-using environments for the reduction of use and
subsequent harms. Environmental prevention intervention programs can be
effective and complement treatment efforts to ameliorate the consequences of
use and substance use disorder.
In this chapter, we will outline some effective environmental approaches to
the prevention of alcohol consequences with a focus upon what can be done to
ameliorate them in community settings. While environmental prevention efforts
to reduce tobacco and other substance use have begun in earnest over the past
decade (6), much can be learned from a focus on alcohol. After a statement of
the scope of the problem, we will distinguish environmental approaches from
other approaches to prevention. We will review the growing scientific bases for
these prevention efforts. We will then summarize current knowledge and best
practices for community prevention efforts aimed at reducing alcohol-related
consequences among youth and adults who drink.
SCOPE OF THE PROBLEM
Unhealthy alcohol use is a serious and significant public health issue. Nearly 88
000 people (~62 000 men and 26 000 women) die in the United States from
alcohol-related causes each year, making alcohol use the third leading
preventable cause of death (7). This corresponds to 2.5 million years of potential
life lost annually from alcohol-related causes, the cost of which was estimated to
be $249 billion in 2010 (8,9). Furthermore, excessive drinking among underage
youth is responsible for at least 4300 deaths each year, and cost the U.S. $24
billion in 2010 (8). Overall, the social and health costs attributable to alcohol far
exceed those of illicit drugs with large disparities in costs related to alcohol use
across communities and locales (10).
Alcohol-related motor vehicle crashes account for many of these deaths.
National Highway Traffic Safety Administration data indicate that at least 29%
of traffic crashes involved alcohol impairment in 2015 and, despite declines in
traffic fatalities, 10 265 people died in 2015 due to alcohol-involved traffic
crashes with the cost of alcohol-involved fatalities estimated at $44 billion (11).
In 2013, 11% of people aged 16 and older reported driving while under the
influence of alcohol at least once in the past year, equivalent to 28.7 million
people in the United States (12).
Alcohol-related deaths are also attributable to a variety of related injury
risks. Depending upon the person’s body weight, gender, and drinking
experience, alcohol use alters motor skills, reaction time, and judgment (13,14)
and increases risk of injury to the person drinking and to others (15). Alcohol
use is involved in a substantial percentage of injuries caused by falls, drownings,
and burns (6,16). Cherpitel and Ye (17) concluded that “no safe level of
consumption appears to exist in relation to injury risk.”
Alcohol use is also related to violence and crime. Alcohol has been
estimated to be involved in between 28% and 43% of violent injuries (18) and
47% of homicides (16). Much of the violence associated with drinking takes
place among young people between the ages of 15 and 29, and this sadly
includes high rates of both interpersonal violence (19) and suicide (20). Crosby
et al. (21) found that 24% of suicides involved alcohol intoxication in excess of
0.08% blood alcohol concentration (BAC), and Miller et al. (22) found alcohol
involvement in 27% of hospital discharges recording the survival of a suicide
attempt.
Medical care costs associated with excessive drinking are conservatively
estimated to be $27.4 billion dollars per year, lost productivity related to
drinking accounts for almost five times this amount ($179.3 billion per year),
and costs for law enforcement and criminal justice proceedings due to alcohol-
related crimes are $25 billion per year (8). Crimes attributable to alcohol have
been estimated to cost $84 billion a year (23), more than two times the estimated
$38 billion attributable to illegal drugs. Alcohol-related injuries were estimated
to cost employers $28.6 billion a year in 1998-2000 (24).
ENVIRONMENTAL VERSUS
INDIVIDUAL APPROACHES TO
PREVENTION
Both prevention and treatment are needed to reduce alcohol consequences and
related costs in community settings, the former to reduce use and prevent
unhealthy use and consequences before they begin and the latter to treat alcohol
use disorder once established. Although important, treatment alone cannot
effectively reduce use and consequences related to alcohol. The activities of
commercial alcohol markets help ensure that a large pool of susceptible people
who drink remain at risk for unhealthy alcohol use. A portion of these people
who drink alcohol progress to alcohol use disorder or addiction, only a small
minority of these seek or enter treatment, and relapse rates after treatment are
high (25). The consequence of these dynamics is that treatment would have to be
nearly universally applied and very effective to substantially reduce alcohol use
disorder in drinking populations (26). A more significant concern than the
limited effectiveness and reach of treatment, however, is that most alcohol-
related consequences, and the lion’s share of healthcare and social costs related
to alcohol use, arise among people who drink alcohol but neither drink heavily
nor have an alcohol use disorder (17). Treatment is not indicated for these people
who drink alcohol. Prevention efforts are essential to reduce risky alcohol use
before an alcohol use disorder is established (27).
Many educational prevention programs have been implemented that attempt
to inform people about the effects of alcohol and consequences of use, encourage
people to abstain from use, or encourage the development of social norms that
discourage risky use. Given the narrow focus of early preventive programs on
education to the exclusion of other alternatives, incomplete conceptual models of
program effects, poor program design and implementation, and inadequate
evaluation, these earlier programs demonstrated limited success (28–31). More
recently, some preventive interventions focusing on correcting misperceptions
about alcohol use norms have been shown some success in reducing or delaying
alcohol use among young people (32–34), but critical reviews continue to
conclude that there is little convincing evidence that educational programs by
themselves lead to long-term reductions in alcohol use (35–38). It is
unreasonable to expect that educational approaches alone can have a substantial
and lasting impact on unhealthy alcohol use when people are immersed in an
environment in which alcohol is readily available and heavily marketed (39).
Environmental approaches to prevention take an alternative approach,
acknowledging that alcohol consequences result from interactions among
individuals in many social, economic, and community environments (40–42) and
that some features of these environments can be changed to the benefit of
community members (43,44). Environmental approaches have been developed to
complement educational approaches and have been shaped into programs that
communities can implement without direct intervention with specific individuals
(45–48). While differing in details, these programs share a common heritage of
policy, regulatory, and enforcement interventions that attempt to reduce
consequences of substance use by changing the economic, physical, or social
environments in which alcohol or drugs are obtained or used (49,50). The focus
on communities, such as neighborhoods within cities or cities themselves,
recognizes that interventions at this level are likely to be most effective. It is at
the geographic levels of neighborhoods and cities that most community systems
bear upon alcohol use and consequences (40,51). Community systems are those
formal and informal political and social institutions in a community that enable,
but can also be used to prevent, alcohol consequences. They include families,
schools, neighborhood friends and neighbors, markets for alcohol and other
drugs, enforcement agents, treatment systems, and medical care.
Environmental approaches contrast sharply with educational approaches in
at least five respects: First, they seek to change components of community
systems that make the occurrence of substance use consequences more likely.
These may include changes in functions of formal institutions (eg, reducing
hours and days of alcohol sales (52), but may also include efforts to change
informal systems (eg, by making social hosts legally responsible for providing
alcohol to people who drink and are underage) (53). Educational and other
individualized approaches may encourage individual resistance to or desistance
from use, but do not attempt to alter the formal or informal structures that enable
use. Second, media efforts in environmental prevention are generally intended to
motivate gatekeepers to pursue activities that are extensions of their normal
efforts (eg, law enforcement) or increase public awareness of consequences (eg,
underage drinking; driving under the influence [DUI]) and prevention efforts
(eg, compliance checks to prevent alcohol sales to minors; safe ride programs) in
order to mobilize support for structural and system change. In contrast,
traditional educational approaches use media to target individual risk factors to
elicit individual belief and behavior change through persuasion (eg, Just Say No;
This Is your Brain on Drugs). Third, rather than targeting at-risk individuals,
environmental approaches target broader environments and affect populations of
people who use and do not use alcohol or other drugs. Thus, a workplace
intervention may alter workplace policies toward alcohol to reduce use in the
workplace and thus provide greater safety for all employees (54). Since people
who do not use substances often suffer collateral damage from alcohol and other
drug use by others, (55,56) everyone benefits and can be affected by the
program. Fourth, individual educational approaches attempt to reduce the
individual demand for drugs, whereas many environmental approaches focus on
the supply side of substance use. Environmental efforts may include enforcement
activities to reduce the ability of youths to purchase alcohol (57), interdiction
efforts to reduce availability of illicit drugs (58), efforts to target risks related to
sales or service of alcohol (eg, responsible beverage service [RBS] programs)
(59), harm reduction efforts (eg, needle exchange programs) (49), and efforts to
change drug distribution to ameliorate problem hot spots (60). Fifth, as a final
distinction, environmental approaches often focus on acute rather than chronic
consequences related to use. Such consequences include motor vehicle crashes,
injuries, and violence rather than alcohol use per se. Medical conditions related
to use, such as liver cirrhosis, are the outcome of rather long periods of heavy
consumption. Consequences that are proximal to illegal drug markets, such as
drug-related crime (61), or to alcohol markets, such as alcohol-related crashes,
on the other hand, are affected by current acute use and can be prevented without
necessarily affecting use. Thus, a RBS program may reduce sales to intoxicated
patrons in bars and subsequently reduce driving while intoxicated (59), but need
not have an overall effect on drinking to be effective.
DOMAINS OF ENVIRONMENTAL
PREVENTION
Environmental prevention programs act in four domains: the physical, the social,
the economic, and the legal. Prevention programs may alter physical access by
affecting proximity to sources of alcohol, tobacco, and other drugs. College
dormitories may prohibit alcohol in dorm rooms, workplace administrators may
eliminate the sale of tobacco through vending machines, and public markets for
illegal drugs may be disrupted by matrix enforcement programs (49).
Environmental prevention programs may alter social access by affecting the
social networks that encourage and enable informal distribution of alcohol and
other substances. Thus, they may alter social access to alcohol by restricting
social activities at which alcohol is served (eg, during on-campus celebrations),
reduce social access to tobacco through smoke-free policies, or moderate social
access to illegal drugs by establishing and enforcing drug-free zones in a
community. Environmental prevention interventions may alter economic access
by increasing the price and opportunity costs (real costs) associated with
obtaining and using alcohol, tobacco, and other drugs through taxation,
minimum pricing, regulating hours of sale, or changing the economic geography
of availability (eg, restricting outlet density). Increased enforcement of minimum
drinking age laws may increase the opportunity costs to youth for obtaining
alcohol. Reducing the legal BAC for driving may increase the likelihood of
incurring personal and monetary costs associated with drinking and driving.
The four domains of environmental influence interact in producing alcohol
and other drug consequences. The physical, social, economic, and legal
availabilities of alcohol (represented by outlets, use by others, beverage prices,
and the laws regulating such) intersect at places where alcohol consequences
may occur. The presence of other people who are drinking at outlets exposes the
patrons of a bar to social influences for drinking and greater risks of violence
(62). Prices for alcoholic beverages at bars are much greater than at liquor or
grocery stores, changing both the nature of drinking at bars and its relationship
to consequences, such as driving while intoxicated and alcohol-related crashes
(63). The purchasing and consumption patterns of others at these establishments
can influence the behaviors of others by encouraging greater levels of
intoxication (64). Parallel arguments can be constructed for illegal drugs.
Concentrated use of illegal drugs (eg, in and around crack houses) is associated
with substantial degrees of crime and elevated rates of disease (49,65). Prices of
illegal drugs may be influenced by drug interdiction efforts (modestly), but
certainly affect quantities of drug purchases (65). Favored drugs used change as
social access is restructured by enforcement efforts or changes in informal social
systems that support drug distribution (66).
NINE EFFICACY TRIALS
The past three decades have seen the intensive development of community-based
environmental prevention intervention programs to address unhealthy alcohol
use and consequences. Community-based environmental prevention research has
moved from trying to establish that environmental prevention programs can
work to asking questions about what works, for whom, and why? Using a variety
of case-comparison research methods, the early phase of this research
demonstrated that:
1. Marshalling community action through media dissemination, education, and

enforcement campaigns could lead to reductions in drinking and DUI, the
“Saving Lives Program” (67).
2. Alcohol sales to underage youth, underage purchases and use of alcohol, and
drinking and DUI could be reduced through community organization to
monitor sales to youth, underage sales decoy operations at alcohol outlets,
keg registration, policy action to shorten hours of sale for alcohol,
implementation of RBS training programs, sponsorship of alcohol-free
events for youth, and educational programs for youth and adults, the
“Communities Mobilizing for Change on Alcohol (CMCA)” project (68).
3. Media mobilization, RBS programs, reductions in sales to underage youth,
increased enforcement of drinking and DUI laws, and reduced access to
alcohol could together lead to reductions in alcohol involved motor vehicle
crashes, injuries due to assaults, drinking and DUI, and heavy drinking
among adults, the “Community Trials (CT)” project (43).
Clearly, communities can act to reduce alcohol consequences by modifying
community environments. But since different communities have different
environmental structures and needs and different problems and concerns,
each requires some adaptation of program foci in the different domains of
environmental prevention. The current challenge is how to develop and
field an adaptive framework that applies the logic of environmental
prevention to the needs of different communities. This process may be
illustrated by considering six more recent studies.
4. The goal of the Operation Safe Crossing project was to implement and
evaluate a large DUI enforcement program at the US/Mexican border to
reduce the number of youths crossing the border to drink in the city of
Tijuana (across the border from the large metropolitan area of San Diego,
California). The intervention activities for this project included both
enforcement of drinking and driving laws through the use of sobriety
checkpoints near the border and enforcing laws barring youth from leaving
the United States without parents or other adult guardians through special
patrols conducted about every 60 days. Data from a border breath-test
survey were used to dramatize the problem and gain public support for
action. The data were also used to help design the enforcement effort and
measure progress in reducing the cross-border drinking problem. Analysis
of data from this prepost study involved observations on more than 2
million pedestrians returning from Tijuana. The Operation Safe Crossing
program appeared to reduce the number of late-night crossers by 31.6%
relative to rates before the intervention. In addition, the proportion of
pedestrians with blood alcohol concentrations at 0.08 or above declined by
29%, and there was a decline in the number of 16- to 20-year-olds who had
been drinking and were involved in automobile crashes relative to other
drivers of the same age group who had not been drinking and crashed (69).
5. The primary goal of the Sacramento Neighborhood Alcohol Prevention
Project (SNAPP) was to implement and evaluate neighborhood-level
interventions intended to reduce youth and young adult access to alcohol,
risky drinking, and associated consequences, particularly in low-income
ethnically diverse neighborhoods. SNAPP posed three basic questions:
Could an environmental approach be tailored to the unique needs of
economically and ethnically diverse populations? Could environmental
strategies address the problem of intentional injuries (ie, assaultive
violence) in economically and ethnically diverse settings? Finally, could
more specifically tailored interventions be implemented at the
neighborhood level? To address these questions, SNAPP implemented five
interventions to reduce alcohol access, drinking, and related consequences
in two low-income, predominantly ethnic minority neighborhoods, focusing
on individuals between ages 15 and 29; these included a community
mobilization and awareness component, an RBS component, and underage-
access and intoxicated person law enforcement component. These
neighborhood interventions led to an estimated reduction of 3.9% in police
calls related to assaults and a 33.4% reduction in emergency medical
system (eg, ambulance) responses related to motor vehicle crashes in the
first relative to the second intervention site. Subsequently, the project found
an estimated reduction of 36.5% in police calls related to assaults and an
estimated reduction of 37.4% in emergency medical system responses
related to assaults in the second intervention site over preintervention levels
(70).
6. The Stockholm Prevents Alcohol and Drug Problems (STAD) program was
developed in 1996 as a project of the Stockholm, Sweden, City Council and
the Karolinska Institute. The focus of STAD was on preventing risky
alcohol use in restaurants, bars, and nightclubs. The program implemented
a combination of strategies, including community mobilization, RBS
training and practices to prevent overservice, and enforcement. The
program increased service refusal rates to apparently intoxicated patrons
from 5% prior to the program to 70% 5 years later (71). Importantly, there
was a 29% decrease in violent crimes reported to the police in the
intervention area compared with the control area (72). The program also
significantly increased the likelihood that club doormen would refuse
entrance to apparently impaired patrons (73). Even after taking
implementation costs into account, it has been estimated that the STAD
program saved as much as €31 million over 10 years through reductions in
judicial system costs, lost productivity, healthcare costs, and costs
associated with other damage (74).
7. The aim of the Safer California Universities Project was to determine
whether environmental prevention strategies targeting specific off-campus
settings would reduce the incidence of student intoxication on college
campuses. Fourteen large public universities were recruited to participate in
the project, campuses were matched on campus and community
characteristics, and one member of each pair randomly assigned to the
intervention condition. The intervention campuses implemented five
environmental interventions: (a) nuisance party enforcement operations to
reduce problems related to off-campus parties, (b) minor decoy operations
at on- and off-premises outlets to reduce underage sales and sales to
intoxicated persons, (c) police roadside checkpoints testing for intoxicated
drivers, (d) development of local ordinances to discourage nuisance parties
or provision of alcohol to people who are underage in social gatherings, and
(e) the use of campus and local media to increase the visibility of all these
environmental strategies. Significant reductions in the incidence and
likelihood of intoxication at off-campus parties and bars/restaurants were
observed among intervention campuses compared to controls. A lower
likelihood of intoxication was also observed among intervention campuses
for the last time students drank at an off-campus party, a bar or restaurant,
or another (undesignated) setting. No increase in intoxication appeared in
any setting, a sign that heavy drinking and intoxication were not displaced
to other drinking contexts. Finally, stronger intervention effects were
observed at those intervention campuses with the highest intensity of
implementation (75).
8. The Oregon Reducing Youth Access to Alcohol Project incorporated a mix
of law enforcement and other community-based activities to address
underage drinking. Involving 36 communities in the state, the project was
initiated as a collaborative effort involving researchers, local community
members, the Oregon Liquor Control Commission, and the Addictions and
Mental Health Division (AMHD) of Oregon’s Department of Health and
Human Services. The five specific program components were (a)
community mobilization, (b) a reward and reminder program, (c) media
advocacy, (d) enforcement, and (e) coordination and community outreach.
Uniquely, the reward and reminder program educated merchants who could
sell alcohol to minors and checked practices for identifying underage youth
and provided constructive feedback to clerks, managers, and owners when
proper I.D. (identification) checking procedures were not followed. This
effort was combined with media advocacy focusing on topics such as
county-specific underage drinking, underage drinking during prom and
graduation, dangers of underage drinking at home, social host liability, and
law enforcement activities. Enforcement activities included compliance
checks, which were completed once per year for 2 years in each of the off-
premises alcohol outlets in the project communities, along with shoulder
tap operations, third-party purchase surveillance, enforcement of minor in
possession laws, DUI enforcement, and controlled party dispersal. The
project demonstrated significant reductions in underage sales across
intervention communities and reductions in drinking outcomes in
communities with the highest levels of implementation (76).
9. The Study to Prevent Alcohol-Related Consequences (SPARC) was a
comprehensive intervention using a community organizing approach to
implement environmental strategies in and around college campuses to
reduce high-risk drinking and alcohol-related consequences among college
students (77). Eight public and two private universities in North Carolina
were randomized to an intervention or comparison condition. Although
each campus developed its own prevention plan, they were required to
choose three of four strategy domains: (a) reduce alcohol availability, (b)
address price and marketing of alcoholic beverages, (c) improve social
norms, and (d) minimize harm related to alcohol. The interventions were
expected to be comprehensive, including policy, enforcement, and
awareness. Examples of specific components include restricting alcohol at
campus events and enforcing laws prohibiting sales to minors. These
interventions lead to ~228 fewer severe consequences per month on each
campus and 107 fewer injuries caused to others per month. Higher levels of
implementation were associated with reductions in negative consequences
resulting from others’ drinking and in alcohol-related injuries caused to
others.
MULTICOMPONENT ENVIRONMENTAL
APPROACHES CONSIDERED
The studies reviewed above differed along a number of dimensions. Each was
targeted to a slightly different population, implemented in different sites,
involved a different implicit or explicit logic model, targeted different outcomes,
used different evaluation tools (eg, in-school surveys, roadside survey data on
alcohol-related crashes, purchase surveys), and ultimately produced different
findings with different implications for program development and future
research. That said, each was characterized by a common set of core scientific
characteristics. Specifically, each involved careful collection of baseline data,
targeted a well-defined community level problem, involved long-term
implementation and monitoring, and produced a final intervention evaluation
documenting success in reducing the target problem. More substantively, each
was comprehensive and multicomponent, addressed the specifics of the local
alcohol environment, based on prior research, and relied on local energies for
implementation. Importantly, each demonstrated, across a variety of research and
community settings, the potential impact of interventions targeting physical,
economic, social, and legal aspects of the alcohol environment on drinking and
alcohol consequences. Clearly, this history demonstrates that environmental
prevention can work. “What works?” and why it works remain important
questions if we are to develop effective and efficient interventions.
THE EMERGENCE OF ECOLOGIC

RESEARCH
One of the ancillary benefits of these projects has been the development of a set
of core research findings that suggest directions for future environmentally based
preventive interventions. These projects were, indeed, efficacy trials, but
efficacy trials “with a twist” so to speak. Each manipulated multiple components
of complex community systems related to drinking and related consequences.
All attempted to regulate or limit access to alcohol through commercial outlets
or social settings, deter risky drinking through some form of community
mobilization or outreach, encouraged responsible business practices leading to
safer drinking environments, and encouraged enforcement efforts to reduce
consequences of drinking among youth (ie, at social hosted parties) or adults (ie,
driving after drinking). Each produced fundamental research findings on the
intervention practices that can lead to successful environmental preventive
interventions in community settings. Each has also guided the field toward
specific social ecologic studies that will enable us to develop a better
understanding of how community systems work and how to intervene in those
systems to improve community health.
Despite the demonstrated effectiveness of environmentally based preventive
interventions, we can develop better programs by obtaining a more detailed
understanding of how changes in alcohol environments affect individual and
group behaviors related to drinking and consequences. For example, by detailing
specific drinking contexts, and situational and social characteristics of those
contexts, that lead to heavy drinking and consequences, we can better understand
the social ecologic interactions in which we can intervene to reduce adverse
outcomes. A better understanding of the social ecology of drinking and
consequences, the dynamic human-to-human and human-to-environment
interactions that lead to harm, can then help focus prevention efforts and even
suggest novel interventions as well. Two examples will help make clear how we
can proceed: first, it has long been known that the availability of alcohol in the
home, among peers, and through some alcohol outlets can affect youth access to
and use of alcohol (78). But locations where alcohol may be obtained (in the
home, others’ homes, a store) and then used (at home, at a park) vary a great deal
by environmental circumstance and change with age (79), specific contexts are
associated with greater risks for unhealthy alcohol use and related consequences
(80), and specific forms of social or parental control in those contexts can
moderate unhealthy alcohol use in adolescents (81). Second, it has also long
been known that numbers of bars and bar densities are related to assaults among
adults (82). But recently, it has become evident that people who drink heavily
appear to self-select into these drinking environments (83) and that malleable
characteristics both outside (eg, physical disorder, low-income neighborhoods)
and inside these environments (eg, crowding) are related to greater likelihoods of
assault (84). In both these examples, specific recommendations can be made to
moderate heavy drinking among youth and adults with research efforts helping
to direct prevention practitioners address the question, “What works in
community contexts?” This research frontier of environmental approaches to
prevention provides the working link between regulatory practices and
individual behaviors in risky drinking and substance use environments (85,86).
THE LOGIC OF ENVIRONMENTAL

PREVENTION
Even as we continue to build a registry of effective prevention strategies, we are
faced with the awareness that translational research into the most efficient ways
to implement those strategies in community settings is sorely lacking (87).
Conventional approaches to dissemination of environmental approaches rely
upon common understandings of means and goals that are often lacking among
community members. These activities are, for this reason, often very slow and
labor intensive. One approach to facilitate implementation is the use of logic
models to drive the early phases of community interventions. This approach has
evolved from experience with Holder’s Community Trials project (73), the
SNAPP (75), and the Safer California Universities Project (80). The following
Figure 25-1 shows an example developed to address underage drinking. The
model summarizes an extensive literature review of factors related to differences
in community prevalence of underage drinking (see
http://www.pire.org/logicmodels.htm). The diagram can be used in the very first
meeting of the community task force or coalition and guides assessment,
planning, and implementation activities more directly than current practice in
technical assistance. Evidence-based interventions can be laid over the diagram
to show how they work to reduce adverse outcomes. Thus, this logic model is
not simply a codification of the inputs and outputs of a program or intervention
(as logic models are usually defined), but is instead of synthesis of research, a
theory of change, and (eventually) an action plan, all built on the same simple
platform.
Figure 25-1. Example logic model to facilitate
implementation of a community intervention for underage
drinking
Conventional practice provides materials and menus of environmental

intervention options to community groups with little guidance for tying them
into a synergistic whole. A logic model, by contrast, is far more prescriptive and,
in our experience, thereby greatly appreciated by community members. In each
particular application to a problem outcome, it facilitates communication about
the set of relevant prevention strategies and helps explain how they work
together to affect the outcome. The models evolve over the course of each
intervention program as community actors come to grasp the specific goals of a
program and begin to identify complexes of activities that work. Thus, as shown
in Figure 25-2, local prevention practitioners and enforcement agencies in a
recent trial in 24 California cities developed a strategic plan by which
enforcement operations were complemented with activities that enhanced
enforcement visibility to address underage and excessive drinking among
adolescents and young adults (88). Unlike community mobilization approaches,
which advocate that a large group of stakeholders should be recruited as a first
step, logic model approaches encourage recruitment of other community actors
to support and implement specific components of the intervention, without the
need to attend regular meetings or discussions irrelevant to their own area of
responsibility.
Figure 25-2. Local prevention practitioners and enforcement

agencies strategic plan
In sum, the logic models clarify the partnership between researchers and
community members by drawing attention to what research recommends be
done and what local expertise recommends about how to accomplish it. It leads
communities to focus more on objectives than process, moves the community
quickly through assessment and planning so members can be engaged in the
action phase sooner, and, finally, keeps everyone focused on community-level
outcomes.
ENVIRONMENTAL PREVENTION AND

THE ROLE OF THE MEDICAL
PROFESSIONALS
Although environmental prevention is typically cast in contrast to medical
treatment, its relevance to medical practice, broadly conceptualized, can be
substantial in a number of ways ranging from patient treatment protocols to
broader community health policy initiatives. Perhaps, the most obvious
relevancy concerns the gatekeeper function served by medical practitioners
relative to prescription drugs. Medical practitioners, as a part of their social
function, regulate access to prescription medications on a daily and patient-by-
patient basis. Although prescription medications do often circulate through
social networks, even such access relies heavily on the cooperation of medical
personnel who provide access by writing prescriptions. Given the current
problems associated with addictive prescription medicines related to “doctor
shopping,” prescription sharing, and patients receiving multiple prescriptions for
the same medication or medications whose combined use is counter indicated,
the role of medical professionals is substantial. In addition, medical
professionals may lobby their professional associations for the endorsement of
best practices around related to prescribing. Even more globally, medical
professionals are in a unique position to impact the communities by advocating
for healthier environments. Thus, one may argue that at all levels of community
systems, from the actual settings of clinical practices, where physicians can see
the direct impacts of alcohol use on the lives of people who drink, to the boards
that govern medical practices, which can encourage outreach to patients about
unhealthy alcohol use, to macrostructures, which govern community structures
and ultimately produce observed health outcomes, where physician’s public
actions matter, the potential role of medical practitioners is substantial.
GLOSSARY
Alcohol Misuse—Use of risky amounts of alcohol or any alcohol where it is
hazardous or not allowed (eg, driving while intoxicated, drinking by minors,
drinking in places where alcohol is proscribed). May or may not involve
physical dependence or a substance use disorder. This term (“alcohol misuse”) is
often confusing and should generally be avoided. The confusion arises from lack
of clarity regarding whether or not disorder is included; it is often used as a
synonym for risky or hazardous use.
Alcohol-involved consequences (also known as “problems”)—Individual- or
aggregate-level consequences in which alcohol plays a significant contributing
role (eg, drinking and driving, assaults where participants have been drinking).
The term “problem” has fallen out of favor as it is often undefined (has been
used to mean drinking excessively or drinking with consequences with or
without a disorder) and when used in clinical practice is off-putting for patients
and likely contributes to stigma.
Blood Alcohol Concentration (BAC)—Ethanol percentage in blood. DUI is
typically assumed for legal purposes in the United States when BAC ≥ 0.08%.
Compliance Check—Law enforcement activity in which minors are used to
attempt purchases of alcohol to determine whether outlets sell to minors.
Successful purchases may result in fines or license suspension and, in some
states, criminal charges against the clerk or server.
Deregulation—Legal and regulatory changes in the legal alcohol
environment, which reduce or eliminate regulatory control over aspects of
availability, cost, and outlet locations; typically results in increased consumption
and related consequences.
Ecologic research—Research that focuses upon measuring and modeling the
social mechanisms linking individual actions and environmental conditions to
explain alcohol consequences (eg, the use of alcohol in bar settings as it leads to
risks for drunken driving).
Environmental Approach—A broad approach to alcohol consequence
prevention focusing on alteration in the legal, geographic, economic, and social
aspects of the system though which alcohol is distributed. See text for extended
discussion.
Hot spot—Location where consequences of substance use (eg, assaults,
illicit drug use) exceed expected levels.
Logic Model—Conceptual device to direct community resources and action
and naturally occurring processes (eg, law enforcement activities to decrease the
effects of increased outlet densities on drinking and driving) to reduce
community problems.
Mobilization—Community organization efforts designed and implemented
in support of environmental change (eg, community presentations to garner
support for increased DUI enforcement).
Media Advocacy—The strategic use of media to increase support for policy
change or enforcement (eg, letters written to local newspapers arguing for
increased DUI enforcement).
Minor in Possession (MIP) Law—Statute where possession of alcohol by a
minor is sufficient evidence for citation or prosecution.
Multicomponent Program—Intervention program characterized by multiple
activities and several intermediate goals (eg, both DUI reduction and youth
access reduction affecting drinking and driving and underage access to alcohol).
Off-premise Establishment—Alcohol outlet where consumption is intended
to take place at another location (often called carry-away sales).
On-premise Establishment—Alcohol outlet where consumption is intended
to take place at location of sale (often called on-sale).
Overconcentration—Unusually high density of alcohol outlets associated
with alcohol-related consequences and hot spots, typical in urban areas with low
levels of community resources/organization.
Responsible Beverage Service—Training and policy intervention designed
to reduce levels of intoxication and service to minors in on-premise
establishments.
Shoulder Tap—Law enforcement activity, which involves use of minors to
engage conversations with adults in attempts to have them purchase alcohol.
Sobriety Checkpoint—Law enforcement activity involving systematic or
random stops of vehicle traffic to interview drivers for signs/evidence of
intoxication.
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SECTION 4
Overview of Addiction Treatment

CHAPTER 26
Addiction Medicine in America: Its
Birth, Early History, and Current Status
(1750-2018)
Kevin Kunz and William L. White
CHAPTER OUTLINE
Chapter Overview
Introduction
The Birth of Addiction Medicine
Early Professionalism and Medical Advancements (1830-1900)
Demedicalization and the Collapse of Addiction Treatment (1900-1935)
The Rebirth of Addiction Treatment (1935-1970)
Addiction Medicine Comes of Age (1970-2018)
Organized Addiction Medicine Today
CHAPTER OVERVIEW
1. The birthing and organization of addiction medicine have evolved in concert
with advances in neuroscience, public health policy—or lack of such—
physician interest, serial epidemics, endemic substance use, and societal
understanding.
2. Scientific research from the bench to bedside to the community has
informed a modern understanding of addiction as a brain disease for which
prevention and treatment are possible. Terminology, attitudes, and practices
have evolved with increased knowledge allowing the disease and persons
affected by it to benefit from the spectrum of attention and care given to
other diseases with less morbidity and mortality.
3. As is true for many medical fields, the 18th and 19th centuries were
relatively “dark ages” preceding the maturation of science and medical
practice in the 20th century and a new era in practice and organization that
occurred as the century closed and the 21st century opened.
4. Organized medicine increasingly addressed unhealthy substance use and
addiction beginning in the 1950s, when physicians organized the
forerunners of today’s addiction-related medical organizations.
Governmental and healthcare systems followed the lead of physicians.
INTRODUCTION
The recent recognition of addiction medicine by the American Board of Medical
Specialties and the Accreditation Council for Graduate Medical Education
presents a timely backdrop to this review of American physicians’ involvement
in the prevention and treatment of alcohol and other drug-related problems over
the last two centuries. This chapter describes the birth of addiction medicine in
the late 18th century, the professionalization of addiction medicine in the second
half of the 19th century, its virtual collapse in the opening decades of the 20th
century, and its reemergence as a fully legitimized medical subspecialty at the
opening of the 21st century. “What is past is prologue”a is a saying of prescient
value in medicine and public health. This chapter represents history still
evolving and in which the reader is a participant. Indeed, the modern field of
addiction medicine can trace its lineage from the scholars of ancient
civilizations, through Drs. Benjamin Rush, Ruth Fox, Robert Smith, and
American Surgeon Generals to include today some 5000 practicing addiction
physician specialists and thousands of other health professionals across
disciplines who have brought the field to its new standing in mainstream
medicine and health care.
This review includes early pioneers of addiction medicine, conceptual and
clinical breakthroughs, the evolving settings in which addiction medicine was
practiced, the larger currents in American medicine, and the evolving social
policies that influenced the early practice of addiction medicine. That this brief
history ends with the field’s acceptance into the American “House of Medicine”
is especially poignant, as time has amply demonstrated the multisystem
biological, behavioral, and societal impact of unhealthy substance use and
addiction.
THE BIRTH OF ADDICTION MEDICINE

The roots of addiction medicine began not in a young America but in the ancient
civilizations of Africa and Europe. Special methods to care for persons addicted
to alcohol were developed in ancient Egypt, and references to chronic
intoxication as a sickness that enslaved the body and soul date to Herodotus (5th
century BC), Aristotle (384-322 BC), and Seneca (4 BC-65 AD). St. John
Chrysostom (1st century AD) provided one of the earliest comparisons of chronic
alcohol inebriety to other diseasesb (1). These earliest intimations of the concept
of addiction and its treatment reflect the fleeting observations of individuals
rather than an organized cultural response to alcohol and other drug problems.
The earliest American medical responses to alcoholism emerged within the
systems of medicine practiced by Native American tribes. Alcohol-related
problems rose dramatically in Native America as alcohol became increasingly
used as a tool of economic, political, and sexual exploitation in the 18th and
early 19th centuries (2,3). Native tribes actively resisted these problems through
political and legal advocacy, organizing sobriety-based cultural revitalization
movements, and through the medical treatment of those affected. Native
American healers used botanical agents to suppress cravings for alcohol (hop
tea), to induce an aversion to alcohol (the root of the trumpet vine), and to
facilitate personal transformation within sobriety-based cultural and religious
revitalization movements (4).
By the time the American Declaration of Independence was penned in 1776,
there were merging, parallel social trajectories and disruption as alcohol was
used to purchase enslaved Africans to work in the tobacco fields producing the
new nation’s major exported commodity.
In colonial America, there was pervasive consumption of alcoholic
beverages but no recognition of excessive drinking as a distinct medical problem
(5). This changed in response to increased alcohol consumption (a near tripling
of annual per capita alcohol consumption between 1780 and 1830), a shift in
preference from fermented to more potent forms of distilled alcohol, and the
emergence of a pattern of socially disruptive “frontier drinking” (6,7). It was in
this changing context that several prominent Americans “discovered” the
phenomenon of addiction (8).
In 1774, the philanthropist and social reformer Anthony Benezet published a
treatise, Mighty Destroyer Displayed, that recasts alcohol from its status as a gift
from God to that of a “bewitching poison.” He noted the presence of “unhappy
dram-drinkers bound in slavery” and observed that intoxication had a tendency
to self-accelerate: “Drops beget drams, and drams beget more drams, till they
become to be without weight or measure” (9).
Benezet’s warning was followed by a series of publications by Dr. Benjamin
Rush. Rush’s work is particularly important given his prominence in colonial
society and his role in the history of American medicine and psychiatry. Rush’s
1784 pamphlet, Inquiry into the Effects of Ardent Spirits on the Human Mind
and Body, was the first American treatise on alcoholism, and it almost single-
handedly launched the American temperance movement. In this pamphlet, Rush
catalogued the symptoms of acute and chronic intoxication, described the
progressiveness of these symptoms, and suggested that chronic intoxication was
a “disease induced by a vice” (10). Rush was the first prominent physician to
claim that many persons with alcohol addiction could be restored to full health
and responsible citizenship through proper medical treatment and to call for the
creation of a special facility (a “Sober House”) to care for these persons (11).
Rush’s writings were mirrored in the work of physicians in other countries,
most notably the Edinburgh physician Dr. Thomas Trotter, whose 1788
publication, Essay, Medical, Philosophical, and Chemical, on Drunkenness and
Its Effects on the Human Body, shared many of Rush’s ideas (12). Another
contribution that influenced the subsequent development of addiction medicine
in America was the work of Christopher Wilhelm Hufeland, who in 1819
described a clinical condition characterized by uncontrollable cravings for
alcoholic spirits that triggered periodic “drink storms.” Hufeland labeled this
condition dipsomania. During the same decade, Lettsom, Armstrong, and
Pearson described the condition that Thomas Sutton subsequently christened
delirium tremens (13).
By the late 1820s, the subject of chronic intoxication was taken up in a
number of medical dissertations. Most notable among these were the works of
Drs. Daniel Drake and William Sweetser. Drake speculated on the causes of
“habitual drinking” and hinted at what would later become the concepts of
inability to abstain and loss of control (“the habit being once established, he will
not, I almost say cannot, refrain”) (14). In 1828, Sweetser provided a detailed
account of the pathophysiology of chronic alcohol intoxication, including
depictions of the addictiveness of alcohol and the potential role of heredity. He
concluded that intemperance created a “morbid alteration” in nearly all the major
structures and functions of the human body. Cycles of compulsive drinking were
viewed by Sweetser as the product of a devastating paradox: the poison (alcohol)
was itself its only antidote (15).
The 1827 publication of the Reverend Lyman Beecher’s Six Sermons on the
Nature, Occasion, Signs, and Remedy of Intemperance exerted their own
influence on the emerging concept of addiction. Bridging the gap between moral
and medical models, Beecher described the intemperate as being “addicted to the
sin” and suffering from an “insatiable desire for drink.” Beecher also described
the early warning signs of addiction, linking these to the later signs that Rush,
Drake, Sweetser, and others had catalogued. Second, he challenged these very
physicians who, in the case of Rush, had tried to get their patients to moderate
their drinking by switching from distilled alcohol to fermented drinks such as
wine or beer. Beecher’s declaration, “There is no remedy for intemperance but
the cessation of it,” marked the call for complete abstinence as a personal and
social strategy for the resolution of alcohol problems (16).
Between 1774 and 1829, America “discovered” addiction through the
collective observations of her physicians, clergy, and social activists. There was
an emerging view that chronic intoxication was a problem with biological roots
and consequences and thus the province of the physician. These earliest pioneers
declared that chronic intoxication was a diseased state, and they articulated the
major elements of an addiction disease concept: biological predisposition, drug
toxicity, pharmacological tolerance, disease progression, morbid appetite
(craving), loss of volitional control of intake, and the pathophysiological
consequences of sustained alcohol and opiate ingestion. Though their treatments
could involve such “heroic” methods as purging, blistering, bleeding, and the use
of toxic medicines, they also used surprisingly modern strategies (eg, aversive
conditioning) and recognized many pathways to the initiation of sobriety (eg,
from religious conversion to witnessing an alcohol-related death). The writings
of this period portray addiction recovery not as an enduring process but as a
climactic decision. This view focused the attention of the emerging temperance
movement on the pledge of lifetime abstinence (from distilled alcohol) as a
central strategy in early attempts at disease recovery.
Addiction medicine emerged in the shift from its treating medical
consequences to treating the alcohol addiction itself. The earliest practice of
addiction medicine predated institutional treatment and was practiced out of the
private offices of individual physicians. Alcohol was not the only drug of
concern to these physicians. During the 16th and 17th centuries, physicians in
Germany, Holland, Portugal, and England had begun to conceptualize opium as
“a kind of poison” that required regular and increasing use that, when stopped,
created a unique sickness that drove people to return to the drug (17). In 1701,
the English physician John Jones (18) provided a detailed account of opiate
withdrawal in his book, The Mysteries of the Opium Reveal’d. Three events
between the early and mid-19th century profoundly altered the future of
narcoticc addiction in America: the isolation of morphine from opium, the
introduction of the hypodermic syringe, and the emergence of a patent drug
industry. These events produced drugs of greater potency, created a more
efficient and euphorigenic method of drug ingestion, and increased the
availability and promotion of psychoactive drugs (19,20).
a This quotation by William Shakespeare, which in present-day use emphasizes that history sets the context
for the present, is engraved on the National Archives Building in Washington, D.C.
b To preserve the historic perspective of this chapter, terms such as inebriety and intemperance have been
maintained despite their current obsolescence. However, terms such as chronic drunkenness, drunkards,
alcoholic, addict, and others have been updated in an effort to reflect modern terminology and current
understanding of the disease of addiction and the persons afflicted by it (see chapter “2”—reference here the
new terminology chapter).
c “Narcotic” in current medical terminology refers to opioids. It has been used to legally categorize other
substances, including other drugs causing altered mental states, such as stupor.
EARLY PROFESSIONALISM AND

MEDICAL ADVANCEMENTS (1830-1900)
In 1828, Dr. Eli Todd, superintendent of the Hartford Retreat for the Insane,
called for the creation of physician-directed asylums for persons with severe
alcohol addiction. Under his influence, the Connecticut State Medical Society
gave support to this idea in 1830 (21). A year later, Dr. Samuel Woodward,
superintendent at the Hospital for the Insane at Worcester, Massachusetts, wrote
a series of influential essays echoing the Connecticut recommendations. He
declared:
A large proportion of the intemperate in a well-conducted institution

would be radically cured, and would again go into society with health
reestablished, diseased appetites removed, with principles of
temperance well grounded and thoroughly understood, so that they
would be afterwards safe and sober men (22).
Woodward argued that intemperance was a physical disease requiring medical

remedies and, siding with Beecher, declared that “the grand secret of the cure for
intemperance is total abstinence from alcohol in all its forms” (22). This total
abstinence position gained influence in light of the failed efforts to cure
alcoholism through the use of public pledges to refrain only from distilled
alcohol. Indeed, the continuing variant social behaviors resulting from fermented
alcoholic drinks contributed to the temperance movement’s shift from the partial
pledge to the T-total pledge (23).
In the 1830s and 1840s, a series of clinical contributions to the
understanding of chronic intoxication exerted considerable influence on the
emerging field of addiction medicine (24). First, there were new experiments and
clinical observations on the pathophysiology of alcohol, such as those of Prout,
Beaumont, and Percy on the effects of alcohol on the stomach and the blood
(25). Dr. Robert Macnish’s Anatomy of Drunkenness (1835) (26) offered one of
the earliest typologies of alcohol addiction, noting seven clinical subtypes.
Macnish also referenced a subject that continued as a medical controversy for
much of the 19th century: the claimed spontaneous combustion of “alcohol
inebriates” (27,28).
In 1838, France’s leading expert on alcoholism, Dr. Jean-Étienne Dominique
Esquirol, argued that the disease of intemperance was a “monomania”—a
“mental illness whose principal character is an irresistible tendency toward
fermented beverages” (29). This was followed in 1840 by Dr. R.B. Grindrod’s
text, Bacchus, in which he declared “I am more than ever convinced that
drunkenness is a disease, physical as well as moral, and consequently requires
physical as well as moral remedies” (30–32).
One of the most significant milestones in the history of addiction medicine
was the 1849 publication of Magnus Huss’ text, Chronic Alcoholism. After an
extensive review of the chronic effects of intoxication, Huss declared:
These symptoms are formed in such a particular way that they form a disease
group in themselves and thus merit being designated and described as a definite
disease … It is this group of symptoms which I wish to designate by the name
Alcoholismus chronicus (33,34).
Huss’s text stands as the landmark addiction medicine text of the mid-19th
century. It contributed a clinical term—alcoholism—that came into increasing
medical and public popularity in the transition between the 19th and 20th
centuries.
The Washingtonian Revival of the 1840s and the fraternal temperance
societies and reform clubs that followed brought the issue of recovery from
alcoholism onto center cultural stage. Local Washingtonian groups encountering
“hard cases” needing more than an occasional sobriety support meeting began
organizing lodging houses that evolved into America’s first addiction treatment
institutions. A multibranched treatment field emerged in the mid-19th century.
Homes for the chronically inebriated emerged out of mutual aid societies that
viewed addiction recovery as a process of moral reformation (35). There were
medically directed “inebriate asylums,” the first of which was the New York
State Inebriate Asylum, chartered in 1857 and opened in 1864 (36,37). There
were also privately franchised, for-profit addiction cure institutions such as the
Keeley, Neal, Gatlin, and Oppenheimer Institutes. These institutions generated
considerable controversy over their claim to have medicinal specifics that could
cure addiction and their practice of hiring physicians who were in recovery from
addiction (38,39). Homes established by mutual aid societies, asylums, and the
private addiction cure institutes competed with bottled patent medicine addiction
cures (most containing alcohol, opium, morphine, or cocaine), some of which
were promulgated by physicians, and religiously sponsored recovery colonies
and rescue missions (21). By the late 1870s, large urban hospitals, such as
Bellevue Hospital in New York City, had also started opening wards designed to
treat chronic addiction (40). Annual admissions of persons with alcoholism at
Bellevue rose to 4190 by 1895—a number that continued to climb to more than
11 300 per year in the opening decade of the 20th century (21).
In 1870, Dr. Joseph Parrish led the creation of the American Association for
the Cure of Inebriety (AACI), which brought together the heads of America’s
most prominent inebriate homes and asylums. The AACI bylaws posited that:
(a) Intemperance is a disease. (b) It is curable in the same sense that

other diseases are. (c) Its primary cause is a constitutional
susceptibility to the alcoholic impression. (d) This constitutional
tendency may be either inherited or acquired (41).
The AACI published the first specialized medical journal on addiction—the

Journal of Inebriety. The journal, edited by Dr. T. D. Crothers during its entire
publication life (1876-1914), was filled with essays by addiction medicine
specialists and with advertisements promoting various treatment institutions
(42,43). A similar inebriety treatment movement was under way in Europe, and
the first international meetings of addiction medicine specialists were held
during this period (44).
American physicians specializing in addiction began releasing texts on
addiction and treatment methods in the 1860s: Dr. Albert Day’s Methomania: A
Treatise on Alcoholic Poisoning and Dr. W. Marcet’s On Chronic Alcoholic
Intoxication. The production of such literature virtually exploded in the 1880s
and 1890s. Among the most prominent texts either written in America or that
exerted a significant influence on the practice of addiction medicine in America
during this period were Dr. H. H. Kane’s Drugs That Enslave: The Opium,
Morphine, Chloral and Hashish Habits; Dr. Fred Hubbard’s The Opium Habit
and Alcoholism; Dr. Asa Meyerlet’s Notes on the Opium Habit; Dr. T. L.
Wright’s Inebriism; Franklin Clum’s Inebriety: Its Causes, Its Results, Its
Remedy; Dr. T. D. Crothers’ The Disease of Inebriety from Alcohol, Opium and
Other Narcotic Drugs; Dr. Norman Kerr’s Inebriety or Narcomania: Its
Etiology, Pathology, Treatment, and Jurisprudence; and Dr. Charles Palmer’s
Inebriety: Its Source, Prevention, and Cure (21).
The central organizing concept of 19th-century addiction medicine
specialists was that of inebriety. Inebriety was viewed as a disease that
manifested itself in numerous varieties. These varieties were meticulously
detailed by clinical subpopulation and drug choice. Addiction medicine texts
were often organized under such headings as alcoholic inebriety, opium
inebriety, cocaine inebriety, and ether inebriety. Inebriety was viewed as a
disease that sprang from multiple etiological pathways, unfolded in many
diverse patterns, and had a variable course and outcome. Inebriety specialists
talked eloquently about the need to individualize treatment and, by the 1880s,
had begun to recognize and study the problem of posttreatment relapse (45).
The treatment methods of the two physician-directed branches of the
inebriety movement (the inebriate asylums and the private addiction cure
institutes) were quite different, and the conflicts between these branches
reflected allopathic and homeopathic approaches to medicine in this period. The
inebriate asylum physicians advocated a sustained (1-3 years), legally enforced
course of treatment that consisted of withdrawal management, collateral medical
treatments, and a period of institutional convalescence. The addiction cure
institute physicians boasted medicinal specifics (hypodermic injections and
liquid tonics) that could “unpoison” the cells and destroy the craving and
compulsion to use alcohol, opiates, and cocaine—all in 4 short weeks, cash in
advance. Drug treatments within both branches included such substances as
cannabis, cocaine, chloral hydrate, paraldehyde, strychnine, atropine, and
apomorphine. Although some addiction medicine specialists used cocaine as a
tonic during withdrawal management, most warned of the addictive properties of
the drug (21).
Most inebriate asylums and addiction cure institutes treated all drug
addiction, whereas others, such as Dr. Jansen Mattison’s Brooklyn Home for
Habitues (opened in 1891), specialized in the treatment of opiate and cocaine
addiction (46). The inebriety literature of this period is filled with debates over
whether medically supervised opiate withdrawal should be abrupt, rapid (over
days), or sustained (over weeks and months). One also finds discussions of such
contemporary issues as the problems of drug substitution and the management of
the relapsed patient (44).
Understanding of the potential physiological foundations and consequences
of addiction increased during the last two decades of the 19th century. Carl
Wernicke’s 1881 discovery of a psychosis with polyneuritis that resulted from
chronic alcoholism and Sergei Korsakoff’s 1887 description of an alcoholism-
induced psychosis characterized by confusion, memory impairment,
confabulation, hallucinations, and stereotyped and superficial speech both
underscored the potential organic basis of behavior in persons with chronic
alcoholism. There was considerable discussion about the potential hereditary
transmission of inebriety (47).
The American Medical Temperance Association (AMTA) was founded in
Washington, D.C., in 1891 at the annual meeting of the American Medical
Association (AMA). Dr. N. S. Davis of Chicago was its founder and first
president. The AMTA published the Bulletin of the American Medical
Temperance Association under the editorship of Dr. J. H. Kellogg, director of the
Battle Creek Sanitarium (48).
In summary, the field of addiction medicine experienced professionalization
and specialization between 1830 and 1900. There were many addiction medicine
pioneers who founded medically directed treatment institutions, men such as
Turner, Parrish, Crothers, and Day and, later, Dr. Agnes Sparks, one of the first
female physicians specializing in addiction medicine. The practice of addiction
medicine shifted from the private physician’s practice to the institutional setting.
Within this institutional practice, there was a growing understanding of the
physiological consequences of chronic alcoholism and an extension of the
concept of inebriety to embrace dependence upon opium, morphine, cocaine,
chloral hydrate, chloroform, and ether. There was a well-articulated addiction
disease concept with elaborate protocols for withdrawal management and
rehabilitation, though there was considerable conflict between allopathic and
homeopathic approaches to addiction treatment.
The growing field of addiction medicine was infused with optimism in the
early 1890s. Dr. T. D. Crothers proclaimed, “The future looks promising, and it
is believed that the public will support inebriate asylums with increasing
generosity” (49). There were reasons for Crothers’ optimism. There was a new
and feasible disease concept of inebriety and two addiction-related medical
organizations that embraced a field that had grown from a handful of specialized
treatment institutions in 1870 to several hundred by the turn of the century. But
forces outside the medical profession that were stirring would drive a wedge
between the physician and those addicted to alcohol and other drugs.
DEMEDICALIZATION AND THE

COLLAPSE OF ADDICTION
TREATMENT (1900-1935)
There was a further profusion of addiction medicine texts in the first decade of
the 20th century: J. B. Mattison’s The Mattison Method in Morphinism: A
Modern and Humane Treatment of the Morphine Disease; T. D. Crothers’ The
Drug Habits and Their Treatment; T. D. Crothers’ Morphinism; and George
Cutten’s The Psychology of Alcoholism. The proliferation of addiction literature
could not hide the fact that America’s response to alcohol and other drug
problems was shifting. Between 1900 and 1920, addiction treatment institutions
closed in great numbers in the wake of a weakened infrastructure of the field,
rising therapeutic pessimism, economic austerity triggered by unexpected
depressions, and a major shift in national policy. The country turned its gaze to
state and national prohibition laws as the solution to alcohol and other drug-
related problems.
As inebriate homes, asylums, and the private addiction cure institutes closed
in tandem with the spread of local and state prohibition laws, persons with
alcoholism were relegated to other institutions. These included the “foul wards”
of large city hospitals, the backward of aging state psychiatric asylums, and the
local psychopathic hospital, all of which did everything possible to discourage
admission for the treatment of alcoholism. Wealthy persons with alcoholism or
other addiction sought discrete withdrawal management in a new genre of
private hospitals or sanitariums. These latter institutions were known as “dip
shops” (from dipsomania), “jitter joints,” or “jag farms” (21). There were also
efforts to integrate medicine, religion, and psychology in the treatment of
alcoholism, most notably within the Emmanuel Clinics in New England (50).
For all but the most affluent, the management of alcoholism shifted from a
strategy of treatment to a strategy of control and punishment via inebriate penal
colonies. The large public hospitals also bore much of the responsibility for the
medical care of chronic alcoholism (51).
The shift from viewing the alcohol addicted person as a person with a
disease in need of help to a person of weak character was reflected in the
medical literature of the early 20th century. Kurtz and Kraepelin coined the term
alcohol addiction to depict those whose will was “not strong enough to abandon
the use of alcohol even if drinking causes them serious economic, social and
somatic changes” (34). Addiction medicine organizations struggled in this
shifting cultural climate. The AMTA and the American Association for the Study
and Cure of Inebriety merged in 1904 to create the American Medical Society
for the Study of Alcohol and Other Narcotics. In 1907, the Journal of Inebriety
merged with The Archives of Physiological Therapy. This marked the
progressive demise of both the Journal of Inebriety and its parent organization.
The last issue of the Journal of Inebriety was published in 1914, and the
American Association for the Study and Cure of Inebriety collapsed in the early
1920s after a subsequent sharp decline in demand for treatment after passage of
The National Prohibition Act, also known as the Volstead Act, which
promulgated prohibition in keeping with the 18th Amendment of the U.S.
Constitution. Alcohol-related problems decreased dramatically in the early
1920s but rose to preprohibition levels by the late 1920s (21). The 18th
Amendment transferred cultural ownership of alcohol problems from physicians
to law enforcement authorities. A similar process was underway with drugs other
than alcohol, but it took two decades for this shift in approach to fully emerge.
Early 20th-century addiction texts by physicians such as George Pettey and
Ernest Bishop boldly proclaimed that narcotic addiction was a disease, and Dr.
Foster Kennedy in 1914 declared that morphinism was “a disease, in the
majority of cases, initiated, sustained and left uncured by members of the
medical profession” (52–54). An early cohort of physicians had already begun
operationalizing this addiction disease concept by advocating and offering clinic-
directed withdrawal management and maintenance for persons with “incurable”
narcotic addiction (55–58). The medical treatment of persons addicted to
narcotics was dramatically altered by passage of the Harrison Anti-Narcotic Act
of 1914. This federal act designated physicians and pharmacists as the
gatekeepers for the distribution of opioids and cocaine. Although this law was
not presented as a prohibition law, a series of Supreme Court interpretations of
the Harrison Act (particularly the 1919 Webb vs. the United States case) declared
that for a physician to maintain a person with addiction on his or her customary
dose is not “good faith” medical practice under the Harrison Act and therefore
an indictable offense (19).
Despite the federal mandate against prescribing narcotics to dependent
persons, physicians in 44 communities operated morphine maintenance clinics
between 1919 and 1924. These clinics, which were sponsored by local health
departments and even local police departments, all eventually closed under the
threat of federal indictment (19–21). The Harrison Act, in effect if not intent,
transferred responsibility for the care of addicted persons from physicians to
criminal syndicates and the criminal justice system by threatening physicians
with both loss of license and incarceration if they provided maintenance rather
than rapid withdrawal management of addicted persons (59).
Physician culpability in the problem of addiction to opioids made it difficult
for the AMA to oppose this government infringement in medical practice. In
1919, the AMA passed a resolution opposing ambulatory treatment, in effect
opposing narcotic maintenance as treatment. There were, however, many
physicians who became harsh critics of the Harrison Act and this new era of
criminalization. Such criticism was reflected in the new addiction medicine texts
that emerged in the 1920s, such as Dr. Ernest Bishop’s The Narcotic Drug
Problem and Dr. E. H. Williams’ Opiate Addiction: Its Handling and Treatment
(60–62).
The influence of psychiatry on the characterization and treatment of
addiction increased in tandem with the decline of a specialized field of addiction
medicine. Karl Abraham’s 1908 essay, The Psychological Relations between
Sexuality and Alcoholism, marked the shift from seeing alcoholism as a primary
medical disorder to seeing the condition as a symptom of underlying psychiatric
disturbance (63). Abraham’s essay marked a long series of psychoanalytic
writings that viewed alcoholism as a manifestation of latent homosexuality. In
the mid-1920s, a Public Health Service psychiatrist, Dr. Lawrence Kolb,
published a series of articles challenging earlier physiological explanations of
narcotic addiction. Kolb portrayed addiction as a product of defects in
personality—a characterization that reflected the growing portrayal of addicted
persons as psychopathic and constitutionally inferior (64). The first American
Standard Classified Nomenclature of Disease (1933) included the diagnoses of
“alcohol addiction,” “alcoholism without psychosis,” and “drug addiction” and
classified these conditions as personality disorders (65).
Few institutional resources existed for the treatment of alcoholism and
narcotic addiction during the 1920s and early 1930s, but the growing visibility of
these problems began to generate new proposals for their management. The
opening of the California Narcotics Hospital at Spadra in 1928 marked the
beginning of state support for addiction treatment (66). Physicians working
within the federal prison system were writing about the problems posed by a
growing population of incarcerated persons with addiction and advocating more
specialized treatment of these individuals (67).
There were important addiction-related research studies in the 1920s. Drs.
Arthur B. Light and Edward G. Torrance conducted research on opioid addiction
at the Philadelphia General Hospital under the auspices of the Philadelphia
Committee for the Clinical Study of Opium Addiction Research. They
demonstrated that withdrawal from opiates is not life-threatening and usually not
dangerous—a finding that was misused by policy makers to withhold medical
care for persons addicted to opioids (68). In 1928, the Bureau of Social Hygiene
published Charles Terry and Mildred Pellens’ work, The Opium Problem (69). In
this important report, Terry and Pellens made a strong argument in favor of
opioid maintenance therapy as the most appropriate treatment for persons not
able to sustain abstinence. Their views were viciously attacked, and it would
only be years later that The Opium Problem would be recognized as one of the
best treatises on opiate addiction ever written (57).
Medical treatments for addiction to narcotics in the first three decades of the
20th century continued to focus on managing the mechanics of narcotic
withdrawal. Heroin was briefly used for withdrawal management from
morphine, and its subsequent emergence as the drug of preference among opioid
addicted persons bred caution in the choice of any narcotic as a withdrawal
agent. This fear of exposing patients to other addicting agents led to the
experimentation with a wide variety of nonnarcotic withdrawal procedures.
These procedures included various belladonna treatments (scopolamine and
hyoscine) that were known to induce hallucinations; peptization treatments
(sodium thiocyanate) that could induce long-lasting psychosis; sleep treatments
(sodium bromide) that had a 20% mortality rate; injected Narcosan, a lipoid
treatment thought to eliminate toxins and stimulate new blood formation but
which actually worsened withdrawal; insulin treatments that had no effect on the
withdrawal process; and serum and blood therapies in which either previously
drawn blood or serum (the latter drawn from induced blisters) was reinjected as
a purported aid to withdrawal management (70–72).
The first decades of the 20th century were marked by a profound therapeutic
pessimism regarding treatment of alcoholism and narcotic addiction. Biological
views of addiction fell out of favor and were replaced by psychiatric and
criminal models that placed the source of addiction within the addicted persons’
character and argued for control and sequestration of this group.
THE REBIRTH OF ADDICTION

TREATMENT (1935-1970)
After the early 20th-century collapse of systems of care for those addicted to
alcohol and other drugs, addiction medicine was revived within the larger
context of two movements.
The “modern alcoholism movement” was ignited by the founding of
Alcoholics Anonymous (1935), a new scientific approach to alcohol problems in
postrepeal America led by the Research Council on Problems of Alcohol (1937)
and the Yale Center of Alcohol Studies (1943) and by a national recovery
advocacy effort led by the National Committee for Education on Alcoholism
(1944). Two goals of this movement were to encourage local hospitals to
detoxify alcohol-dependent patients and to encourage local communities to
establish posthospitalization alcoholism rehabilitation centers (73). The
establishment of a successful community-based noninstitutional mutual support
organization for alcohol use disorders, Alcoholic Anonymous, was cofounded by
Dr. Robert Smith, a physician in recovery from severe alcohol dependence. This
“12-step” prototype and burgeoning movement of broader institutional and
community attention to alcoholism spawned new resources for treatment from
the mid-1940s through the 1960s, including “AA wards” in local hospitals,
model outpatient clinics for alcoholism developed in Connecticut and Georgia,
and a community-based residential model pioneered by three alcoholism
programs in Minnesota: Pioneer House (1948), Hazelden (1949), and Willmar
State Hospital (1950). Dr. Nelson Bradley, who led the developments at Willmar,
later adapted the Minnesota Model for delivery within a community hospital.
That adapted model was franchised throughout the United States in the 1980s via
Parkside Medical Services (74) and was replicated by innumerable hospital-
based treatment programs.
The spread of these models nationally was aided by efforts to legitimize the
work of physicians in the treatment of alcoholism. Early milestones in this
movement included landmark resolutions on alcoholism passed by the AMA
(1952, 1956, 1967) and the American Hospital Association (1944, 1951, 1957)
that paved the way for hospital-based treatment of alcoholism. The former were
championed by Dr. Marvin Block, chairman of the AMA’s first Committee on
Alcoholism. Midcentury alcoholism treatments included nutritional therapies,
brief experiments with chemical and electroconvulsive therapies, psychosurgery,
and new drug therapies, including the use of disulfiram (Antabuse), stimulants,
sedatives, tranquilizers, and lysergic acid diethylamide (LSD) (21).
A mid–20th-century reform movement advocating medical rather than penal
treatment of the opioid-dependent person also helped spawn the rebirth of
addiction medicine. This began with the founding of state-sponsored addiction
treatment hospitals and led to the creation of two U.S. Public Health Hospitals
within the Bureau of Prisons—one in Lexington, Kentucky (1935), and the other
in Fort Worth, Texas (1938). Many of the pioneers of modern addiction medicine
and addiction research—Drs. Marie Nyswander, Jerry Jaffe, George Vaillant, and
Patrick Hughes—received their initial training at these facilities. The
documentation of relapse rates after community reentry from Lexington and Fort
Worth confirmed the need for community-based treatment. Three replicable
models of treatment emerged: therapeutic communities directed by persons in
sustained recovery, methadone maintenance pioneered by Drs. Vincent Dole and
Marie Nyswander, and outpatient drug-free counseling (21).
State and federal funding for alcoholism and addiction treatment slowly
increased from the late 1940s through the 1960s and was followed by landmark
legislation in the early 1970s that created the National Institute on Alcohol
Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse
(NIDA)—the beginning of the federal, state, and local community partnership
that has been the foundation of modern addiction treatment. Parallel efforts were
under way to provide insurance coverage for the treatment of alcoholism and
other drug dependencies. The expansion of such insurance coverage in the 1960s
and 1970s and the establishment of accreditation standards for addiction
treatment programs by the Joint Commission on Accreditation of Hospitals set
the stage for the dramatic growth of hospital-based and freestanding, private
addiction treatment programs in the 1980s. NIAAA and NIDA also made heavy
investments in research that led to dramatic breakthroughs in understanding the
neurobiology of addiction that encouraged more medicalized approaches to
severe alcohol and other drug problems (75–77).
The growing sophistication of addiction science was aided by other key
organizations. The College on Problems of Drug Dependence, which dates from
the Committee on Problems of Drug Dependence established in 1929, hosts an
annual scientific meeting and publishes the journal Drug and Alcohol
Dependence. The Research Society on Alcoholism, founded in 1976, also holds
an annual scientific conference and publishes the journal Alcoholism: Clinical
and Experimental Research.
ADDICTION MEDICINE COMES OF AGE

(1970-2018)
Many factors were involved with the modernization of organized addiction
medicine practice. Insights from basic, clinical, and epidemiological science and
the availability of evidence-based prevention and treatment interventions
provided new understanding and tools. The pioneering brain imaging studies of
Volkow and others (78) demonstrated even to the casual observer that addiction
was more than a moral failing, behavioral, or criminal problem. Elucidating the
addicted brain neurocircuitry also suggested prevention and intervention
strategies. These imaging studies added to the emerging consensus that
substance use disorder is a unified etiological and diagnostic disease state and
that subclassifications based on the particular substances used, although useful,
are insufficient. A further insight from neuroimaging is that so-called behavioral
addiction, such as gambling and some eating disorders, appears to involve the
same brain neurocircuitry as addictive substances. Thus, these disorders, which
represent significant medical and public health problems, are being increasingly
addressed by physician addiction specialists. Another example of cross-
substance commonality is the early work of Dr. Heather Ashton (79) who
through close clinical attention described in detail a protracted withdrawal
syndrome from benzodiazepines. This was followed by reports of an often
similar protracted withdrawal syndrome from other substance classes. Perhaps
the cap to the unified theory of addiction came from the Nobel Laureate Dr. Paul
Greengard, who was able to demonstrate the role of the protein DARPP-32 in
the actions of multiple dependence producing drugs (80). Finally, the unified
view of substance use disorders is exemplified in the 2016 Surgeon General’s
Report on Alcohol, Drugs, and Health: Facing Addiction in America (81).
Previous U.S. Surgeon General Reports had focused only on tobacco/nicotine,
and most reports from the National Institutes of Health were also substance
specific. In the 2016 report, Surgeon General Vivek Murthy addressed all
nontobacco/nicotine substances (there were two recent tobacco/nicotine and
health reports, in 2014 and 2016).
Also occurring and adding to a shift in appreciation for drugs in American
culture has been a series of highly visible American drug use crises and
controversies with which society and medicine have had serial struggles: heroin
use by US soldiers in Vietnam, the powder and crack cocaine epidemics,
regional methamphetamine epidemics, and scientific and public consideration of
tobacco and cannabis use. Perhaps no substance use disorder better represents
the potential for the critical role of medicine and physicians in attenuating
substance use harm as that of tobacco use over the last 60 years. The direct
medical consequences of tobacco use are still responsible for more than 480,000
annual deaths in America. Yet, beginning with the first Surgeon General’s Report
on Tobacco in 1954 and carrying through this last decade, both the prevalence of
tobacco use and the public’s acceptance of it has plummeted. Contrasting with
this is the changing status of cannabis from an illicit to a licit substance and even
as a medication made licit legislatively. As we bring this history to the present, it
must unfortunately be noted that beginning in the 1990s, another devastating
prescription opioid epidemic began its sweep across America. For this later
epidemic, still raging at the time this chapter was written, the words of Dr. Foster
Kennedy 100 years ago are worth repeating. Opioid addiction is, he said, “a
disease, in the majority of cases, initiated, sustained and left uncured by
members of the medical profession.” Whereas physician culpability in the
previous opioid epidemic made it difficult for organized medicine to oppose a
criminal justice solution in the early 1900s, in 2016-2017, organized medicine
responded by addressing the complicity of physicians in the modern opioid
epidemic by advancing physician credentialing and training in addiction
medicine. Thus, the current response of medicine brought physicians into the
solution, rather than defaulting to a historically flawed and ineffective criminal
justice approach. This response helped usher addiction medicine into new
relevance and importance in medicine and public health.
ORGANIZED ADDICTION MEDICINE
TODAY
Addiction medicine as an organized subspecialty of medical practice has been
significantly advanced by six entities: the American Society of Addiction
Medicine (ASAM), the American Academy of Addiction Psychiatry (AAAP),
the American Board of Addiction Medicine (ABAM), The Addiction Medicine
Foundation (TAMF), the American Board of Preventive Medicine (ABPM), and
the Addiction Medicine Fellowship Directors Association (AMFDA).
The American Society of Addiction Medicine

The American Society of Addiction Medicine can trace its roots to the
establishment of the New York City Medical Committee on Alcoholism in 1951
and the 1954 founding of the New York State Medical Society on Alcoholism
under the leadership of Dr. Ruth Fox, which in 1967 established itself as a
national organization—the American Medical Society on Alcoholism (AMSA).
AMSA evolved into the AMSA and Other Drug Dependencies and then into the
ASAM.
ASAM’s achievements include the following:
Gaining ASAM membership in the AMA House of Delegates, as a national

medical specialty society (achieved in June 1988)
Advocating the AMA’s addition of addiction medicine to its list of
designated specialties (achieved in June 1990)
Offering a certification and recertification process for addiction medicine
specialists based on the early work of the California Society of Addiction
Medicine
Hosting its Annual Medical–Scientific Conference, State of the Art Course,
Review Course, and a variety of other continuing education courses
Publishing the following:
The ASAM Patient Placement Criteria
The Principles of Addiction Medicine, now in its sixth edition
The Essentials of Addiction Medicine, with two previous editions
Publishing first the Journal of Addictive Diseases and presently the Journal
of Addiction Medicine
The ASAM Standards of Care for the Addiction Specialist Physician
Effectively advocating for national policies to broaden access to care
Convening a Medical Specialty Action Group in 2006, which produced
recommendations for the formal acceptance of addiction medicine as a
specialized field of practice and the subsequent facilitation and
encouragement for the new independent American Board of Addiction
Medicine
In addition to a broad range of community physicians, academic leaders, and

researchers who fostered the early growth of ASAM, many physicians who
found recovery from addiction also became interested in the science, prevention,
and treatment of substance use disorders and became ASAM members and
leaders. As the science of addiction advanced and evidence-based treatments
became available, a younger generation of physicians who observed negative
outcomes within their own families, acquaintances, and patients with substance-
related problems became interested in the field without having direct personal
experience. Today, ASAM has a membership of over 4000 practitioners,
teachers, administrators, and researchers.
The American Academy of Addiction

Psychiatrists
The AAAP (formerly the American Academy of Psychiatrists in Alcoholism and
the Addictions) was established in 1985 with the goal of elevating the quality of
clinical practice in addiction psychiatry. The AAAP’s contributions include
successfully advocating that the American Board of Psychiatry and Neurology
grant addiction psychiatry (ADP) subspecialty status (1991) to psychiatrists who
meet the eligibility criteria and administering an ADP certification and
maintenance of certification (MOC) process. As of December 2016, there were
1189 ABPN diplomates holding active subspecialty certification in ADP, with an
annual average of 45 new certificants from 2006 through 2016. One of the
leaders of the new field of addiction psychiatry, Dr. Sheldon Miller, also
envisioned the eventual creation of addiction subspecialties in other medical
disciplines. He noted that a subspecialty does not just produce clinical experts to
care for the most difficult cases but also produce well-trained educators and
researchers. He wrote that “…medicine is a field that listens to its own
subspecialists. This is true of every specialty: if there is a subspecialty group
within the organization, it has an important voice which simply doesn’t exist in
organizations that do not have such subspecialties.” “I offer this as a model and a
challenge to other specialties, so that their boards, their Residency Review
Committees, their professional organizations, might come together and hopefully
do some of the same things as the field of addiction psychiatry” (77). It is the
pioneering and enduring work of AAAP and the leadership of the ADP
subspecialty that set the stage for all physicians to meet medicine’s responsibility
for the prevention and treatment of substance use disorders.
AAAP hosts an annual conference on addiction psychiatry and publishes the
American Journal on Addictions as well as a wide variety of addiction-specific
publications. The AAAP promotes fellowships in addiction psychiatry (82).
The American Board of Addiction Medicine

By 2006, ASAM had held as an organizational priority for nearly three decades
the acceptance of addiction medicine within the “House of Medicine,” primarily
recognition of the field by the American Board of Medical Specialties (ABMS).
On three occasions since the 1980s, ASAM explored pathways for bringing
addiction medicine forward through formal recognition as a specialized field of
practice by the ABMS. Recognition by ABMS of a subspecialty indicates special
expertise is necessary to practice in the field. Certification of a physician by an
ABMS member board signifies that the physician has achieved the highest
measurable American standard for competency in a field. The ASAM Directors
believed that ABMS recognition was critical in bringing the field to its greatest
benefit in advancing patient care and the public health. The ASAM leadership
understood that if patients were to have access to qualified addiction medicine
physicians and that if health systems and insurers were to offer and compensate
addiction medicine services, then training and credentialing standards would
need to be established as they are for other medical fields. Addiction medicine
would thus have to become an ABMS and Accreditation Council for Graduate
Medical Education (ACGME) a recognized field for physician certification and
training.
The ABMS itself was established in 1934 for the purpose of certifying
physician competence in an era where there were no standard measurements or
credentials by which patients or society could judge the qualifications of medical
practitioners. The medical marketplace was unregulated and often dangerous: the
public had no way of benchmarking a physician’s skills. ABMS initially
accepted primary specialties for inclusion, and by 1972, the first 10
subspecialties were recognized. In 2016, ABMS recognized and, through its 24
member boards, had certified 860,000 physicians in 37 general certificate fields
and 87 subspecialty fields. At the time of this text, addiction medicine was the
most recently recognized subspecialty (www.abms.org).
Another certifying entity is the American Osteopathic Association (AOA),
which was established in 1897 for osteopathic physicians (Doctors of
Osteopathic Medicine). The AOA currently offers certification in 18 specialties,
and as of the last available certification report, there were 102 137 osteopathic
physicians in the United States, and of these, 33% held active AOA certification
and an additional group held active ABMS certification
(http://www.osteopathic.org/inside-aoa/about/aoa-annual-
statistics/Pages/default.aspx). An AOA subspecialty certificate in addiction
medicine is available, although until 2017 <10 physicians were granted this
certification due to the absence of fellowship training opportunities. In 2017, the
AOA began granting addiction medicine status to active AOA certificants who
held active ABAM diplomate status, and as of the date of this publication, ~100
physicians hold AOA addiction medicine certification.
ASAM was aware that recognition by ABMS would launch the field into full
membership and participation in American medicine and health care, setting the
stage for the availability of prevention and treatment services by identifiable,
qualified physicians. ABMS recognition would bring four critical avenues of
parity to the prevention and treatment of unhealthy substance use and addiction:
availability of addiction prevention and care services equivalent to those of other
disease states, availability of physicians who can attend to these medical
conditions, patient payment coverage for addiction medicine services through
third parties on par with other conditions, and reimbursement to physicians,
systems, and others who provide specialized addiction medicine services.
Without parity in these dimensions, patients with unhealthy substance use and
addiction would not benefit from the many available evidence-based prevention
and treatment modalities catalogued in other chapters of this text.
Although the initial explorations by ASAM did not lead to ABMS
recognition of addiction medicine, these efforts were critical precedents of the
eventual formal recognition and acceptance of the field. As a result, in 2006,
under the leadership of ASAM President Dr. Elizabeth Howell and acting on a
comprehensive set of recommendations by ASAM’s Medical Specialty Action
Group, the ASAM directors unanimously voted to “encourage and assist” in the
establishment of a new independent entity to bring addiction medicine into
formal recognition by ABMS.
Thus, in 2007, the American Board of Addiction Medicine—a freestanding
and independent organization—was incorporated as a nonprofit entity for the
purposes of: promoting the public welfare by contributing to the improvement of
the quality of care in the medical specialty of addiction medicine; establishing
and maintaining standards of excellence in the field; establishing and
maintaining standards and procedures for certification and MOC; granting to
qualified physicians documents certifying that they are Diplomates of the Board;
granting and issuing other documentation of recognition of special knowledge
and skills in addiction medicine; suspending or revoking diplomate certificates;
serve the public, physicians, hospitals, and other healthcare organizations by
furnishing lists of the Diplomates of the Board; communicating to and with
health professional and relevant organizations the importance of the standards,
certification, and practice in addiction medicine as a means to confirm and
advance the quality of care received by patients with substance use disorders.
In 2009, ASAM transferred its addiction medicine certification examination
to ABAM. The ABAM Credentials Committee set the exam eligibility criteria to
be consistent with the other national licensure, training, and experience
requirements. The ABAM certification examination was continuously updated
by collaboration between the National Board of Medical Examiners (NBME)
and the ABAM Examination Committee. Clinical relevance was added to the
evaluation process for all questions, and the committee was enlarged to assure
that the content of the examination reflected the range of issues faced by
addiction medicine physicians, including medical and psychiatric complications
observed across all medical specialties. Committee members included physicians
from the specialties most usually encountering substance use disorders and their
complications and basic and clinical scientists. Applicants for the examination
were accepted from all medical specialties, with significant representation from
psychiatry, family medicine, and internal medicine. ABAM certified just over
4000 physicians between 2009 and 2016.
ABAM Maintenance of Certification

To assure that ABAM diplomates remain current with developments in the field
of addiction medicine, the ABAM MOC Committee launched the ABAM MOC
Program in 2009. Diplomates annually enroll in Part I to validate their
unrestricted medical license and Part II to meet lifelong learning requirements
through addiction medicine CME activities (including review and assessment of
journal articles chosen by a panel of addiction medicine experts) were required
to take the Part III “recertification exam” cognitive examination every 10 years
and to enroll in Part IV (Practice Performance Assessment) beginning in 2017,
with the requirement to complete a Practice Improvement Module every 5 years.
By December 2016, 3500 ABAM diplomates were enrolled in the ABAM MOC
program. The MOC participation rate of 87% was considered laudable for a field
which was not yet ABMS recognized.
Certification of physicians by an ABMS member board and ACGME
accreditation of postgraduate physician training (residencies and fellowships) are
the highest standard of measurement for physician competencies and training in
a field. Acquisition of these recognitions is an acknowledgment that the field is
meeting the highest available training and practice certification standards, thus
expanding the pool of physicians who can provide specialty care to patients with
substance use disorders. Thus, the goals of gaining ABMS level certification of
physicians who practice addiction medicine and accreditation of addiction
medicine fellowships by the Accreditation Council for Graduate Medical
Education (ACGME) were critical to advancing the field. ABMS board
certification in addiction medicine could become available to physicians of all
specialties, complementing the certification of psychiatrists in addiction
psychiatry approved by the ABMS in 1991 and bringing to reality a vision
inspired by the establishment of the subspecialty of addiction psychiatry by the
ABPN.
The ABAM certification and MOC processes were developed and executed
in the format of and with the standards promulgated by ABMS, thus setting up
the recognition of the field within this room of the “House of Medicine.”
With the formal ABMS recognition of addiction medicine in 2016, ABAM
discontinued its certification exam, to be administered in the future by the
ABMS member board, the ABPM.

The Addiction Medicine Foundation (TAMF, formerly the ABAM Foundation)
was incorporated in 2007 as a nonprofit entity to support the advance of
addiction medicine through (a) defining the field of addiction medicine and
developing and accrediting addiction medicine fellowships, (b) advancing
eventual ABMS and ACGME recognition of addiction medicine, (c) promoting
prevention as a core principle for the field, and (d) aligning key stakeholders in
medicine, government, philanthropy, and public health in collaborative activities
to more successfully address substance use disorders and their sequelae.
Defining the Field
In July 2010, TAMF held a retreat attended by representatives of government,
academic medical education, prevention, treatment, and research organizations
in the field; directors of fellowship programs in addiction medicine, addiction
psychiatry, internal medicine, family medicine, and pediatrics; clinicians and
trainees (residents); and clinicians in these and other specialties, including pain
medicine. The purpose of the meeting was to construct the documents that define
addiction medicine and its training programs. Core documents of a new field
include the core competencies, educational objectives, core content, scope of
practice, training program requirements, and training program accreditation
policies and procedures.
The documents produced include the Addiction Medicine Scope of Practice,
Addiction Medicine Core Content, and Core Competencies for Addiction
Medicine: Compendium of Educational Objectives for Addiction Medicine
Fellowship Training Program Requirements for Graduate Medical Education in
Addiction Medicine and the Program Accreditation Application Form (PAAF)
(www.addictionmedicinefoundation.org).
Accredited Addiction Medicine Fellowships

The Addiction Medicine Foundation fostered the development of the nation’s
first addiction medicine fellowship programs, which they accredited until
ACGME accreditation of addiction medicine training became available in early
2018. Fifty (50) fellowships of 12-month or longer duration were accredited by
the TAMF between March 2011 and December 2017. A list of these programs
can be found on the TAMF website (www.addicitonmedicinefoundation.org).
dACGME terminology previously aggregated all postgraduate training under the term "residency." Current
ACGME terminology recognizes the 3 to 6 years of specialty field training after medical school as a
residency and postresidency training as a fellowship.
The first addiction medicine fellowship was accredited by TAMF in 2011,

and by December 2017, a total of 160 physicians had graduated from TAMF
accredited programs. Graduated fellows are majority family medicine physicians
and internists yet include pediatricians, psychiatrists, obstetrician–gynecologists,
preventive medicine physicians, anesthesiologists, and others. Sixty fellows
entered the 2017-2018 fellow cohort. The program directors are primarily
psychiatrists, family medicine physicians, and internists. Fourteen programs
have a parallel addiction psychiatry fellowship at their institution. A preliminary
survey of graduated fellows indicated that (a) the majority are internists and
family medicine physicians; (b) fellows were generally young career physicians,
usually entering the fellowship within 10 years of completing a primary
residency; (c) fellows had a high likelihood of remaining at the institution they
trained in and in the state where they trained; and (d) the numbers of female and
male fellows were almost equal, a contrast to the existing pool of ABAM
diplomates who are mostly male.
A problem not unique to fellowships in a new field is currently being
addressed at the national level: securing adequate funding for the start-up and
maintenance of a sufficient number of programs. TAMF has estimated that 125
addiction medicine fellowships will be needed to train an adequate workforce of
addiction medicine subspecialists.
The American Board of Preventive Medicine:

Home to Addiction Medicine
The early successes of the newly revitalized field of addiction medicine led to
optimism that an enduring new medical field of medical practice could be firmly
established (83). Preparing for recognition of addiction medicine by the ABMS
and the ACGME, TAMF Directors interfaced with ABMS and its member
boards from 2008 through 2016 to promote the readiness of the field of addiction
medicine to become the 38th general primary ABMS field. However, this
pathway was neither feasible nor available. Therefore, TAMF Directors met with
the leadership of multiple ABMS member boards to explore the possibility of an
addiction medicine multispecialty subspecialty. The TAMF leadership also
explored with the leadership of ACGME the requirements and process for
meeting ACGME’s high fellowship training standards.
In 2014 at the request of TAMF, the ABPM, an ABMS member board,
agreed to review the readiness of the field to acquire ABMS recognition,
possibly through the sponsorship of the ABPM. For acceptance as an ABMS
field, addiction medicine would have to demonstrate a sufficient group of
credentialed physicians practicing in the field, a complete set of addiction
medicine competencies and educational content, detailed program requirements
for fellowship accreditation, a sufficient number of established fellowships, and
the support of multiple medical and public health organizations, associations,
and academic medical institutions. With these prerequisites met, ABPM began
the process of seeking ABMS recognition of the field. In May 2015, ABPM’s
President, Dr. Denece Kesler, submitted to ABMS an application for the new
field, and in March 2016, ABMS announced recognition of addiction medicine
as a multispecialty subspecialty.
The first annual ABPM addiction medicine certifying exam, open to current
ABMS diplomates from any field, was administered in October 2017. Thirteen
hundred (1300) physicians passed the exam and began the first ABMS level
diplomates in the new field. During the first 5 years, the ABPM certification
exam is administered, “time in practice” in the field of addiction medicine is an
alternative to fellowship training. During this 5-year ABPM Practice Pathway,
applicants without a fellowship who can demonstrate sufficient practice time in
addiction medicine—at least 1920 hours over the previous 5 years—will not
need to have completed an addiction medicine fellowship.
With the transition of certification in addiction medicine passing from
ABAM to ABPM, ABAM no longer offered a certification exam. The American
Osteopathic Association has offered, as mentioned above, to ABAM diplomates,
who are current AOA certificants, AOA addiction medicine certification. ABAM
diplomates who are not eligible for the ABMS or AOA certification pathway are
able to maintain ABAM certification indefinitely by maintaining currency in
ABAM MOC.
The Addiction Medicine Fellowship Directors

Association
The independent AMFDA incorporated in 2016. Its mission is “to promote
excellence in the education and training of current and future generations of
physicians in evidence-based practices in the prevention and treatment of
substance related-complications including addiction.” AMFDA holds an annual
meeting actively promoting training standards in the field.
Accreditation of Addiction Medicine

Fellowships by the Accreditation Council for
Graduate Medical Education (ACGME)
In December 2015, ABPM submitted an application to ACGME for recognition
of addiction medicine as a field for which fellowship training could be
accredited by ACGME. ACGME “is an independent, not-for-profit, physician-
led organization that sets and monitors the professional educational standards
essential in preparing physicians to deliver safe, high-quality medical care to all
Americans” (84). ACGME is the “gold standard” accreditation of all post–
medical school physician training in the United States.
In June 2016, ACGME announced that it would initiate the process to offer
accreditation to addiction medicine fellowship training programs. The first
programs would apply for accreditation in early 2018. When ACGME
accreditation becomes available, TAMF will stop accrediting new programs and
instead will encourage and assist currently accredited TAMF fellowships and
other interested institutions to obtain ACGME accreditation. TAMF has stated an
objective of assisting in the establishment of 125 ACGME accredited
fellowships by 2025.
Finally, several other historical initiatives should be mentioned that have
advanced addiction-related medical education. The NIAAA and the NIDA have
been a continuous force in the field since their establishment, bringing state and
federal government and academic and community physicians into effective
collaborative partnerships. In 1971, these institutes created the Career Teacher
Program (1971-1981) that developed addiction-related curricula for the training
of physicians in 59 US medical schools. In 1976, career teachers and others
involved in addiction-related medical education and research established the
Association for Medical Education and Research in Substance Abuse
(AMERSA). AMERSA draws its members primarily from American medical
school faculty, hosts an annual meeting, and publishes the journal Substance
Abuse.
As this history has reviewed, addiction medicine rose in the United States in
the mid-19th century, collapsed in the opening decades of the 20th century, yet
reemerged and became increasingly professionalized in the late 20th century.
Now, at the opening of the 21st century, addiction medicine has been formally
recognized and accepted within the “House of Medicine.” The field is now
positioned to integrate the prevention and treatment of unhealthy substance use
and addiction into health care and public health systems nationally.
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CHAPTER 27
Treatment of Unhealthy Alcohol Use:
An Overview
Mark Willenbring and Brian Grahan
CHAPTER OUTLINE
Introduction
The Spectrum of Severity in Unhealthy Alcohol Use
Modern Approaches to Treatment
Defining the Problem: What are Treatment Outcomes?
Measuring Drinking Outcomes
Tailoring Treatment to the Continuum of Severity
Treatment and Behavior Change
Systems of Care
Integrating the Evidence and Personalizing Practice
INTRODUCTION
For millennia, alcohol has been one of the most popular and dangerous
substances ingested by humans. Inevitably, some individuals drink too much,
causing themselves and society harm. However, other than purely custodial care,
professional treatment only began in the middle of the 20th century. Since then,
knowledge of the nature, course, and treatment of unhealthy alcohol use rapidly
evolved. Consequently, the evidence base upon which alcohol treatment rests is
considerable and broad, as good as or better than that for many other common
complex disorders.
Indeed, considerable progress toward more humane and effective treatment
has been made in a relatively short time. Nevertheless, the history of treatment
for unhealthy alcohol use presents some unique obstacles that have proved
resistant to reform. A large majority of community programs only offer the
Minnesota Model for the treatment of alcohol use disorder (AUD) in a form little
different from that in 1955 (1–3). In most cases, physician involvement is
limited to treating withdrawal. Furthermore, programs usually offer a time-
limited treatment focused on inducing and maintaining early remission and offer
little except repetition for patients who do not respond. Treatment failure is often
attributed to a patient’s lack of “motivation” or “insight,” rather than to
shortcomings in the therapeutic approach (2,4). For example, why would 30 days
of lectures, low-level counseling, and an introduction to Alcoholics Anonymous
(AA) be expected to change the course of a chronic illness? While often reported
as evidence based, the quality of counseling in community programs is poor,
consisting of casual talk unrelated to therapy (5,6), and supervision is minimal.
Integration with healthcare systems is rare, so identification and management of
coexisting mental and physical disorders is uncommon and highly fragmented,
despite the high prevalence and societal cost of such conditions in treatment-
seeking populations (4,7,8). Few community treatment programs offer
pharmacotherapy for AUD, and most fail to educate their patients about it (2).
Because of these and other shortfalls, lifetime exposure to professional treatment
for AUD is <10%, a figure that has not changed in 30 years. In sum, although
progress has been made, much more remains to be done. Without a major change
in how, where, and by whom treatment is delivered, research findings will
remain unimplemented and unavailable to the patients and families who need
them.
This chapter provides an overview of current research on treatment for
unhealthy alcohol use. The various behavioral and pharmacological treatments
are addressed in detail in other chapters of this textbook. The goal of this
overview is to provide a context to help guide interpretation of the research and
guidelines provided in other chapters. First, an overview of the spectrum of
alcohol use is presented. The effect of diagnostic changes from Diagnostic and
Statistical Manual of Mental Disorders (DSM)-IV to DSM-5 help ground later
discussions in a common framework. Then, we briefly review the history of
therapy for AUD and ways of measuring alcohol use to contextualize potential
treatment goals. Next, we propose a continuum of care that corresponds to the
spectrum of alcohol use and comment on how it may relate to mechanisms of
behavior change. We describe how changes in healthcare policy are affecting the
treatment infrastructure for changing drinking behavior. Finally, we conclude by
exploring how research findings may be applied to individual patients, that is,
the art of evidence-based medicine.
THE SPECTRUM OF SEVERITY IN

UNHEALTHY ALCOHOL USE
Recent research has provided a new and more complete view of the range of
drinking, AUD, and alcohol-related harms in the community. However, some
definitions are needed to understand drinking behavior and relate it to adverse
events. In the United States, a “standard drink” is defined as the amount of
ethanol in 1.5 oz (45 mL) of 80-proof spirits, 12 oz of beer, or 5 oz of table wine,
each containing about 14.5 g of absolute ethanol (see Table 27-1).
TABLE 27-1 Volume of Common Beverages Containing
About 14.5 g of Absolute Ethanol (A US “Standard
Drink”) and the Maximum Recommended Drinking
Limits from The National Institute on Alcohol Abuse
and Alcoholism
aAnd those 65 or older.
Since actual alcohol levels in beer and wine vary, these amounts are meant to be
approximate. A “standard drink” varies widely across the world, and there is no
universal definition. For example, in the United Kingdom and Australia, a
drinking “unit” is defined as 30 mL (1 oz) of 80-proof spirits, equal to about 10 g
of absolute ethanol. Thus, for cross-national comparisons, it is best to focus on
grams of absolute ethanol (per day, per drink, etc.). The National Institute of
Alcohol Abuse and Alcoholism (NIAAA) recommends that men drink no more
than 4 drinks per day and 14 drinks per week and that women (and those 65 and
older) drink no more than 3 drinks per day and 7 drinks per week (Table 27-1).
Drinking within these limits is considered “lower-risk” drinking. Lower limits or
abstinence may be indicated in the presence of coexisting medical or psychiatric
disorders, in older people, or when medication interactions are a concern.
Women who are pregnant or at risk of becoming pregnant are advised to abstain.
In this chapter, a day on which the limit is exceeded is considered a “heavy
drinking day,” and “heavy drinking” is defined as drinking more than the
maximum limits on a regular basis, such as exceeding the daily limits weekly or
more often. Drinking more than advised itself is not considered a disorder.
Instead, DSM-5 recommends that drinking causes “clinically significant
impairment or distress” and that an individual endorses at least 2 out of 11
diagnostic criteria for AUD to make a diagnosis (9). Drinking more than the
recommended limits in the absence of a disorder is considered “at-risk drinking.”
Interpretation of most previous studies of epidemiology and treatment of
AUD has been complicated by changes in diagnostic criteria from DSM-IV to
DSM-5 (9,10). DSM-IV defined two separate alcohol-related disorders: alcohol
abuse and alcohol dependence. Criteria for alcohol abuse focused on severe
external consequences of drinking, such as physically hazardous use, legal and
interpersonal problems, and role failure (failure to meet social obligations as a
student, as a parent, or at work, etc.). Alcohol dependence was focused on
criteria indicating compulsive use (ie, impaired control), tolerance, and
withdrawal. Research after the publication of DSM-IV demonstrated that instead
of two separate disorders, the evidence best supported a single disorder model
(11,12). Thus, DSM-5 AUD includes 10 of the 11 DSM-IV criteria; legal
problems were dropped and craving was added. DSM-5 AUD varies only by
severity of disorder. The number of criteria met is a good reflection of severity
and disability related to drinking (13).
However, some recent research has added considerable uncertainty regarding
the prevalence of AUD. The NIAAA Epidemiological Study on Alcohol and
Related Conditions (NESARC-III), conducted in 2011–2012, has produced
findings at substantial variance from other national surveys, and some of its
findings are simply difficult to interpret and reconcile with each other. Although
some investigators have issued opinions that there is good concordance between
DSM-IV and DSM-5 (14), other published findings note marked shifts between
various groups defined by each diagnostic system. Nearly half of people with
DSM-IV alcohol abuse have no DSM-5 diagnosis, while others have mild AUD,
and some even have severe AUD. Conversely, people with no DSM-IV
diagnosis make up more than half of those with mild DSM-5 AUD. Almost half
of people with DSM-IV alcohol dependence have mild DSM-5 AUD, while the
remainder has moderate to severe AUD. Thus, there is little concordance
between DSM-IV and DSM-5 diagnoses, except that a diagnosis of DSM-IV
alcohol dependence resulted in some type of DSM-5 AUD diagnosis (15). This
makes it very difficult to interpret a past diagnosis of DSM-IV AUD in terms of
DSM-5.
Even more striking, NESARC-III found an unprecedented increase in AUD
prevalence since NESARC-I. Using DSM-IV criteria, 12-month and lifetime
prevalence between NESARC-I (2001–2002) and NESARC-III (2011–2012)
went from 8.5% and 30.1%, respectively, to 12.7% and 43.6%, a nearly 50%
increase in a 10-year time span. Drinking, especially heavy episodic (binge)
drinking, has increased in the United States in recent years (16), which may at
least partially account for the dramatic increase in prevalence. However, two
other national surveys have found stable rates of DSM-IV diagnoses from 2002
to 2012 (NSDUH; (17)). In addition, DSM-5 rates for 12-month and lifetime
prevalence in NESARC-III were 13.9% and 29.1%. Why 12-month rates would
be similar between DSM-IV and DSM-5, but lifetime prevalence would be
widely disparate is unknown. Additional research is needed to reconcile the
contradictory results. Regardless of such discrepancies, unhealthy alcohol use
and AUD result in a significant disease burden (18). How to approach the range
of drinking behaviors and their comorbid conditions will be the subject of the
remainder of this chapter.
MODERN APPROACHES TO
TREATMENT
Professional treatment for AUD that is supported by a base of basic and clinical
research is a relatively new field compared to other areas of medicine. It is
helpful to understand the historical context of our current treatment and outcome
paradigms to understand opportunities and controversies within the field.
For most of history, only custodial treatment for AUD was available.
Modern behavioral treatment approaches grew out of AA on one hand and the
growth of academic psychiatry and psychology after World War II on the other.
AA rapidly spread from its roots in an evangelical Christian movement in 1935,
publishing its Big Book in 1939 (19). The 12 Steps of AA, counseling, and
education were combined to create the “Minnesota Model” of treatment in the
1950s in a collaboration between providers at Willmar State Hospital, the
Pioneer House, and Hazelden—the latter two early AA recovery centers. In
1961, Dan Anderson, a cocreator of the model, became the CEO of the Hazelden
Foundation, an organization that has been influential in its popularization (20).
The Johnson Institute, another Minnesota organization, was established in 1966
to help spread the Minnesota Model; it also developed the procedure known as
an intervention, where people close to someone with a severe AUD come
together to share their concern (and usually shuttle the soon-to-be patient off to a
program). Subsequently, the Minnesota Model has been adopted internationally,
and it is the most prevalent form of treatment available in the United States. For
most US residents, programs based on the Minnesota Model are the only
available approach to treatment (1,2,20).
Key features of the Minnesota Model are the use of both professional staff
and individuals with a personal history of AUD to provide group counseling as
well as patient and family education (2,21). Model programs also include a
strong linkage to AA, a requirement of abstinence from all psychoactive
substances other than tobacco and caffeine, and belief that alcoholism is a
“primary, progressive disease that cannot be cured, although it can be arrested
through abstinence and AA.” It was initially provided only in 28-day programs
in hospitals or residential facilities but is now provided in a wider range of
durations and settings. These programs are often referred to as rehabilitation
(“rehab”) programs. Twelve-Step Facilitation is a manualized version of the
Minnesota Model that has been adapted for research using an individual
outpatient approach (22). Note that 12-step facilitation resembles community 12-
step programs in its focus on AA and abstinence. It is different in many other
ways, including using individual counseling by highly trained and supervised
therapists with advance clinical training. In contrast, community programs are
almost completely group-based, and the counselors have minimal training and
no meaningful supervision. Thus, it is difficult to generalize from studies of 12-
step facilitation to community-based 12-step rehabilitation programs.
The fields of psychology and psychiatry have undergone substantial
development and expansion as well, primarily because the Veterans
Administration (VA) rapidly expanded mental health services following World
War II (23). Pavlov discovered classical conditioning in the 1920s (24), and B.F.
Skinner first published on operant conditioning in 1935 (25). The concepts of
group therapy and therapeutic community were first proposed in the mid-1940s,
with subsequent development and spread in the 1950s and 1960s (26). Albert
Ellis developed the first type of cognitive–behavior therapy, Rational-Emotive
Therapy, in the mid-1950s (27), and Aaron Beck developed cognitive therapy for
depression in the 1960s (28). Specific therapies for AUD based on these earlier
psychological theories include therapeutic communities, aversion therapy,
cognitive–behavior therapy, skills training, community reinforcement, and
contingency management (26). More recently, William Miller and colleagues
developed an approach, motivational enhancement therapy, based on stages of
change and encouraging motivation to change (29). There are several others that
have some evidence of effectiveness, although most studies are small and have a
high potential for bias (such as the originator of the therapy serving as principal
investigator). Manualization and sophisticated monitoring of the application of
behavioral techniques have allowed true comparisons of efficacy with a high
degree of confidence in the validity of the trials. The main conclusion from this
work is that a variety of validated therapy approaches and techniques all produce
similar outcomes (30). Thus, the best therapy approach is to use the most
relevant aspects of all available therapies, rather than focusing on one type over
others. This approach allows greater individualization based on patient
preferences.
Pharmacotherapy for AUD has experienced halting advancement. Many
older psychiatric medications have been tested including lithium carbonate,
anxiolytics, tricyclic antidepressants, antipsychotics, and phenytoin. Although
initial open-label studies for many reported efficacy, subsequent research for all
except disulfiram failed to substantiate early claims. Disulfiram was approved
for use in the United States as a deterrent agent in 1949. It took until 1995 for the
next medication, naltrexone, to be approved by the US Food and Drug
Administration (FDA) for treatment of AUD. Since then, acamprosate and an
injectable depot formulation of naltrexone have been FDA approved, and other
primary or adjuvant agents including topiramate, varenicline, baclofen, and
gabapentin have demonstrated variable degrees of efficacy in randomized
controlled trials (31–35). Available antirelapse medications have a degree of
efficacy in reducing risk of recurrences similar to antidepressants for major
depression, statins for prevention of coronary events, and nonsteroidal anti-
inflammatory drugs for arthritis pain. Potentially novel targets, such as the
central brain stress response system, endocannabinoid receptors, modulators of
AMPA receptors, and the immune system, have been identified. It is likely that
we will continue to see new medications and treatment modalities brought to
market in the next decade. More details on specific medications are provided in
other chapters of this text.
Research on the nature, causes, consequences, and course of AUD has also
grown. Major advances have been made in identifying genetic, developmental,
and environmental risk factors for AUD and describing its natural history and
treatment response, as well as biopsychosocial consequences of heavy drinking
and AUD. Excellent animal models continue to underpin research on the
biological mechanisms underlying behavior. The clinical criteria defining AUD
and its relationship to the timing, frequency, and quantity of heavy drinking have
evolved (9,12). However, it has become apparent that we understand little about
the underlying processes of behavior change in drinking or other behaviors.
DEFINING THE PROBLEM: WHAT ARE

TREATMENT OUTCOMES?
The primary goal of treatment for AUD is reduction of alcohol use. However,
given the cultural heritage of treatment in the United States, as well as the range
of beliefs around the origins of addiction, achieving consensus on specific
treatment goals and more comprehensive outcome definitions has been difficult.
Topics in these debates include the nature of addictive behavior, the role of
spirituality in recovery, and the relationship of specific drinking behaviors to
functional outcomes. Commonly considered outcomes are drinking behavior, the
number of positive diagnostic criteria of AUD, functional consequences of
drinking, and “recovery” versus abstinence or remission (the absence of a
disease once present).
Drinking behavior is the most common outcome of interest. The oldest
conceptual definition of treatment success is continuous, lifelong abstinence.
The origins of this belief are complex, but it emerged in part from the belief
among puritanical American Protestants that only through lifelong abstinence
could a habitual “drunkard” attain moral redemption and salvation. Indeed, it
was to his experience with the evangelical Christian Oxford Group that Bill
Wilson attributed his “hot flash” of spiritual awakening, his subsequent
abstinence, and later many aspects of AA’s 12 steps (19,36). The AA community
still considers any return to drinking to be an absolute failure, requiring the
individual to restart his or her recovery process. Beyond these cultural roots,
more recent work suggests abstinence may be the pattern of drinking most likely
to prevent a recurrence of AUD symptoms for many people in remission,
especially among older patients with severe AUD (37).
Abstinence is not always mandatory, though. Controlled drinking may be a
reasonable treatment outcome for people with milder AUD. Originally grounded
in theories of addiction as a learned behavior, controlled drinking approaches
were developed and compared to abstinence-based approaches amidst
considerable controversy and outright animosity (38–41). Nonabstinent
remission is characterized by drinking within the lower risk limits and endorsing
no criteria for AUD. As the heterogeneity and trajectories of drinking behaviors
among people with a lifetime diagnosis of AUD have been better defined, it has
become clear that nonabstinent recovery is a common outcome, especially
among people who do not seek treatment (42,43). The transition from heavy to
lower-risk drinking often takes years, frequently involving multiple quit attempts
(37,43–46). Among people in nonabstinent remission, psychosocial outcomes
are comparable to those among abstainers (47). The likelihood of achieving
nonabstinent remission is inversely related to the severity of AUD (43).
The impact of alcohol use on medical and psychiatric outcomes, including
all-cause mortality, seems closely tied to the frequency and quantity consumed
(48–53). A recent study on the global burden of disease found that alcohol was
the sixth leading cause of disability globally, including a 41% increase in
attributable mortality and a 31% increase in disability-adjusted life-years since
1990 (54). In the United States, the disease burden from alcohol use, compared
to all other health conditions, was ranked sixth in 2013 (54). More premature
deaths are due to acute events related to alcohol intoxication (56%) with the
remainder due to sequelae of chronic heavy alcohol use (55). From a medical
perspective, it follows that a reasonable treatment goal would be to reduce the
frequency and/or volume of alcohol consumed, regardless of whether abstinence
is an explicit goal of the patient, like the exposure reduction goals of treatment
for diabetes and hypertension. Indeed, even among people with moderate to
severe AUD, all-cause mortality is reduced with decreases in alcohol
consumption (50). These studies do not support a dualistic view of outcomes.
They suggest that working with patients to achieve any reduction in drinking is
better than doing nothing.
Complicating matters, alcohol consumption may provide benefits at lower
risk levels. Lower risk alcohol consumption in middle-aged adults is associated
with decreased incidence of cardiovascular disease and death, diabetes,
Alzheimer disease, and stroke, although heavy drinking increases risk for these
disorders in some studies (56–58). Thus, one must subtract potential beneficial
effects of drinking from potential risk for adverse events when developing risk
estimates.
Compared to measures of consumption, the presence or absence of DSM-5
diagnostic criteria for AUD are less frequently discussed as a measure of
treatment success. Using the DSM criteria (59), full remission is defined as no
longer meeting any of the 11 criteria of AUD, and someone in partial remission
meets one AUD criterion but not enough to qualify for an AUD diagnosis. Note
that the quantity and frequency of alcohol use is not a criterion. Indeed,
nonabstinent remission turns out to be the most common outcome 20 years after
onset of DSM-IV alcohol dependence, followed by abstinence, regardless of
treatment status (43). Interestingly, some population studies have suggested that
the severity of AUD, independent of alcohol consumption, is the dominant
driver of mortality among drinkers (60–62). However, most direct estimates of
mortality among people with AUDs have been obtained with samples of people
seeking treatment. In this group, annual mortality is 1.4-4.7 times that of
matched controls (50,63,64). Since treatment seekers have more severe AUD, a
higher prevalence of comorbid conditions, and less social capital than do non–
treatment seekers, information obtained by studying treatment populations
applies only to the small proportion of people with severe, recurring AUD
(44,65,66). Consequently, there is a need for additional research into multilevel
outcomes that include drinking behaviors, symptoms of AUD, and disability (67)
among community dwellers who have not sought treatment.
Social consequences are mediated by comorbid mental disorders, especially
antisocial personality disorder, and social context. Societies vary markedly in
their tolerance for various forms of behavior associated with intoxication or
AUD. For example, whether an individual is arrested for driving while
intoxicated depends on laws and how they are enforced. However, social
problems associated with alcohol use are strongly related to mortality, the health
of drinkers’ family and friends, as well as their quality of life (13,62,68). In large
community samples, as the number of diagnostic criteria met increased,
disability increased, and functional impairment for severe DSM-IV Alcohol
Dependence (6-7 criteria met) was similar to that for anxiety disorders and
depression (13,46).
“Recovery” has a particular meaning within Twelve-Step ideology.
Abstinence is required but is not sufficient for “recovery.” Not precisely defined,
“recovery” seems to include improved health, personal and spiritual growth,
personal integrity (truth-telling) and contributing to society. Surveys of people
self-identifying as “being in recovery” support this broader view of “recovery”
(69,70). This view was most common among respondents with more severe
AUD histories who sought treatment in Twelve-Step rehabilitation programs. It
was less common among respondents in nonabstinent recovery and those who
had not sought treatment (71–73). It seems best to focus on achieving remission
from AUD (either abstinent or nonabstinent), along with maximizing functional
outcomes. “Recovery” as used in Twelve-Step groups may be useful to those
who affiliate with them but does not have broad relevance across the spectrum of
AUD severity and outcomes.
MEASURING DRINKING OUTCOMES

Methods for measuring drinking behavior and how it affects other outcomes
have advanced significantly, with structured retrospective self-report being the
most common tool. This approach is used in most treatment trials, and research
supports its validity and reliability (74). The most common instrument used is
the Timeline Follow-Back (41,75–77). Using methods that collect data in real
time using interactive voice response, personal digital assistants (eg,
smartphones), and ecological momentary assessment reduced memory errors by
minimizing the time and distractions between drinking episodes and reporting
(78,79). Paradoxically, reporting drinking behaviors daily may independently
lead to reductions in use (80). Most commercial smartphone apps marketed to
assess drinking behavior actually encourage drinking and frequently
overestimate blood alcohol concentration (BAC) (81), though more rigorously
developed programs have significant promise as both measurement and
intervention tools (82–84).
Some laboratory tests are promising. Serum or exhaled alcohol
concentrations continue to be useful markers of alcohol consumption in the
hours before the test is performed. The refinement of biosensors that measure
BAC transcutaneously may improve accuracy in the assessment of drinking
behavior (85,86) but may also cause decreases in drinking. Other traditional lab
tests and calculations such as gamma-glutaryltransferase (GGT), mean
corpuscular volume (MCV), and the ratio of aspartate aminotransferase (AST) to
alanine aminotransferase (ALT) all have poor test characteristics and may be
elevated or altered by other common liver conditions (87). They should not be
relied upon in clinical practice to detect or monitor unhealthy alcohol use. More
promising clinical measures include ethyl glucuronide (EtG), ethyl succinate
(EtS), percent carbohydrate-deficient transferrin (%CDT), and
phosphatidylethanol (PEth). EtG and EtS are minor nonoxidative metabolites of
alcohol that are most concentrated in urine but may be detected in various body
fluids, tissue, and hair beginning a few hours after alcohol consumption (88).
They can be detected in the blood for up to 36 hours and in the urine for up to 5
days. Urine EtG/EtS can detect a broad dose range of ethanol, although
sensitivity is dose and time dependent (89–91). PEth, a phospholipid formed
only in the presence of ethanol, can reflect exposure to alcohol over a 3-week
window (92–94). While a blood sample of PEth may reflect single episodes of
heavy drinking using liquid chromatography and mass spectrometry, the
threshold with the best test characteristics makes it a better measure of regular
alcohol use (95). CDT refers to a transferrin polypeptide that lacks a
carbohydrate chain, the loss of which occurs after moderate to heavy drinking
for several days. %CDT is the percentage of CDT (most commonly
disialotransferrin) found in a blood specimen divided by total transferrin. CDT
levels return to normal within ~2 weeks of drinking cessation (88). By contrast
to EtG/EtS and PEth, the creation of CDT is not specific to ethanol exposure.
Conditions that may affect it include female gender, pregnancy, elevated body
mass index, cirrhosis, and smoking tobacco (96). EtG/EtS are the best
biomarkers of any alcohol consumption in the past few days, while PEth has the
highest sensitivity for the detection of regular alcohol consumption. PEth is
generally positive about twice as often as CDT, even though they are reasonably
well correlated, likely reflecting the large intra- and interindividual variability
inherent in CDT measurements (89). Caution must be observed in using any of
these tests, however, particularly EtG/EtS and PEth. None of the biomarkers
have adequate sensitivity and specificity to detect low to moderate drinking
levels. Even at high levels, systematic self-report is more accurate (97). High-
quality studies of sensitivity and specificity by multiple investigators at different
sites are badly needed. Until more research is done, a “positive” should be taken
as suggestive and requires clinical confirmation.
In early treatment studies of AUD, drinking behavior was grouped into
dichotomous categories of abstinence or drinking. Over time, these simple
categories were supplanted by more complex variable-based approaches, where
average values of a continuous drinking variable were compared among groups
using increasingly sophisticated statistical techniques. Percent days abstinent and
percent days heavy drinking are common examples. This variable-centered
approach has advantages, such as using more data and allowing use of
parametric statistics, thus increasing statistical power. This approach also allows
for a wider range of outcomes to be considered, as discussed above.
However, variable-based approaches will not capture individual
heterogeneity within the study population if only mean values are considered. In
many treatment trials, a portion of the study population will demonstrate a
response but the majority may not respond at all. A robust response in a minority
of individuals may only move the average outcome a small distance, suggesting
that the treatment is only minimally effective overall (which is true for the study
population overall). Variable-centered analyses using either a dichotomous
measure or means of a continuous drinking measure are not designed to capture
such an effect.
Trajectory analyses have the capacity to characterize groups who have a
differential response to treatment. For example, in a reanalysis of two studies of
naltrexone, both of which were unable to detect a treatment effect compared to
placebo with the a priori mean variable-based analysis, trajectory analysis found
that naltrexone recipients were significantly more likely to be in an abstinent
trajectory (98). Trajectory analysis also yields results that are more clinically
intuitive. One such analysis examined three different trajectories through the
follow-up period: stable remission, stable nonremission, and unstable (99), and
another considered both the duration of abstinence and the rate of risky drinking
after a relapse (100). Comparing the likelihood of being in various trajectories
for different treatments is easier for most people to grasp, compared to a change
in a continuous variable such as mean percent days abstinent. Moreover,
trajectory analyses allow for consumption measures to be linked to more abstract
concepts such as quality of life metrics (67,100). Consequently, the use of
various forms of trajectory analysis is likely to increase in the future. Rapid
development in pharmacogenomics suggests the possibility of being able to
identify likely responders to different medications before treatment starts.
However, no genetic marker that practically and reliably predicts a clinically
meaningful response has been identified (101,102).
Interpretation of randomized controlled treatment studies requires
consideration of the mechanism of behavior change and the nature of the control
group. As discussed, there are numerous ways to measure different types of
outcomes during and after intervention. However, what happens before treatment
should not be ignored. Arguably, what happened before a trial starts may best
predict how well a treatment works (103,104). In the COMBINE trial, subjects’
drinking trajectories prior to treatment entry significantly predicted outcome
independent of treatment condition (105). Another large study in the VA
Healthcare System found that brief intervention (the primary independent
variable) likely played no role in the 48% reduction in prevalence of heavy
drinking among patients (106). Keeping this in mind may affect how
policymakers and clinicians apply research results to patients either seeking help
or being mandated to treatment.
TAILORING TREATMENT TO THE

CONTINUUM OF SEVERITY
Multiple treatment modalities have been shown to be effective in the treatment
of AUD. However, the best way to match the type and intensity of treatment to
the individual needs of a patient with AUD remains unclear. For example, no
systematic outcome advantage has been demonstrated for residential or intensive
day program treatment compared to once or twice weekly outpatient treatment
(107). No behavioral treatment has been shown to be better than others that are
conceptually distinct and use different behavioral techniques (108). Attempts to
match specific behavioral therapies with clinical characteristics of patients have
yielded little (108). Several medications are efficacious in reducing relapse or
heavy drinking during early recovery, but none are clearly better than others, and
there is not yet a way to predict how likely a patient is to respond to one rather
than another. Finally, ~10% of people with AUD have a severe chronic form of
the disorder, yet most treatment programs offer a few weeks or months of
treatment, and information on management of AUD as a chronic illness is
limited with mixed results. In sum, current recommendations and practice
regarding the selection and sequencing of treatments are based upon clinical
experience and expert consensus and not randomized controlled trials. In
practical terms, the addiction treatment offered or available likely depends on
patient preference, availability, access, coercion, urgent needs such as imminent
withdrawal or suicide risk, and clinician orientation rather than on scientific
evidence. One of the key research challenges ahead is to develop methods to
compare the effectiveness of different stepwise or adaptive strategies for
deploying treatment modalities with demonstrated efficacy.
In current models, the goal and approach of treatment depends upon the
nature, extent, and severity of the disorder. The continuum of severity as
presented in Figure 27-1 serves as a template upon which to project a continuum
of care.
Figure 27-1 Continuum of severity of AUD. A small

minority fall into severe AUD.
Abstainers, Lower-risk Drinkers, and At-risk

Drinkers
Abstainers and lower-risk drinkers require health promotion, such as education
about the recommended maximum limits adjusted for that person’s individual
situation. Health promotion is especially important for adolescents and women
who are pregnant or at risk of becoming pregnant. The goal for at-risk drinkers is
to reduce consumption, preferably below recommended maximum limits, to
reduce risk of future harm. At-risk drinkers respond well to facilitated self-
change (109) and brief counseling by physicians in primary care, with about a
25% overall reduction in drinking 1 year later, and a greater decrease in heavy
drinking (110,111). Brief counseling in emergency departments or with hospital
inpatients is unclear. Studies vary in their findings. Most find significant
reductions in alcohol use in both brief counseling and comparison groups. Some
studies find between-group differences and some do not. The efficacy of Web or
Internet interventions is also unclear. More research in these areas is needed.
People with Alcohol Use Disorder

Treatment of DSM-5 mild AUD is not well studied. Most studies of treatment of
DSM-IV alcohol dependence have been done on middle-aged, treatment-seeking
adults, especially white males and veterans, who have severe AUD. Thus,
findings from most treatment studies cannot be generalized to the large majority
of adults with AUD. A pressing need is to develop and test treatment approaches
for people with mild to moderate AUD and relatively few comorbidities. In this
type of patient, treatment with oral naltrexone plus brief behavioral support by
healthcare clinicians is at least as effective as state-of-the-art outpatient addiction
therapy (30,112). These findings suggest that pharmacotherapy with medical
management may be an effective approach for patients with similar
characteristics. If so, making such treatment available in primary care and
general psychiatry would substantially increase access to effective care.
About two-thirds of individuals who develop DSM-IV Alcohol Dependence
do so in adolescence or young adulthood. However, only about one-half of them
go on to a chronic course (46). Those who do are more likely to have a family
history of alcohol dependence and antisocial personality traits and to have
started drinking in early adolescence (44). More research on intervening earlier
in the course of illness for those at high risk for chronicity is another priority.
About 40% of dependent persons have midlife onset of mild to moderate AUD,
and those who do are more likely to have coexisting psychopathology and/or a
family history of AUD. This suggests that primary care and general psychiatry
may be ideal settings in which to evaluate strategies to identify and treat this
group.
For those who do not respond to self-change efforts and nonintensive or
brief treatment, referral to specialty addiction treatment is needed. This type of
stepped-care approach is implied in the American Society of Addiction
Medicine’s (ASAM) Criteria (113). However, although the stepped-care
approach makes sense intuitively, it has not been adequately examined for its
effectiveness. Stepped-care or adaptive treatment studies are methodologically
complex and require sophisticated design and analysis as well as large numbers
of subjects. Adaptive study design is an emerging area of interest, however, and
recent advances in statistical techniques make it more feasible. Such research
can help answer questions about the best ways to structure the treatment system
and to most effectively match patient needs and services offered. Attempts to
improve outcomes by matching patient characteristics to treatment type have not
yet yielded information of much use to clinicians, but such a body of knowledge
is likely to develop over time.
For those who do not respond to self-change efforts and nonintensive or
brief treatment, the appropriate next steps are unclear. Since 12-step
rehabilitation is the only other available treatment option in most places, clinical
practice is to refer to one. The ASAM Criteria describe how patients can be
triaged to various intensities of rehabilitation programs and medical care (113).
Although this has helped rehabilitation programs and payers to agree on
placement, the criteria merely reflect current practice and have no scientific
basis. For example, we have known since 1977 that intensive outpatient and/or
residential treatment offers no outcome advantage for AUD over nonintensive
outpatient care (114,115). In general, length of engagement in treatment is a
better predictor of outcome than intensity. There is no empirical basis for
residential rehabilitation, which consists of an intensive outpatient rehabilitation
program in a house (1,116). Although some individuals undoubtedly require
structured sober housing to stabilize, it makes more sense to determine type and
intensity of treatment independent of housing needs.
At the most severe end of the spectrum are those unfortunate individuals
with severe and persistent or recurrent AUD. In this group, coexisting substance,
mental and physical disorders and social disabilities are common, including
antisocial personality, as is a family history of AUD and very early onset. Not
surprisingly, they are the most likely to seek and receive treatment, often due to
overt coercion. Even though most of this group has a chronic or recurrent course,
addiction treatment programs typically offer treatment for only a few weeks or
months. Furthermore, few programs are staffed to address the serious
comorbidities present, so they are often ignored or dealt with through referral
(1,2). The effectiveness of treatment programs for this group is difficult to
evaluate because there are many factors present that may be driving change. For
example, serious physical illness, legal mandates, homelessness, unemployment,
poverty, and family pressure frequently cause or contribute to a decision to seek
treatment. Many of these factors are quite powerful and could account for much
of whatever change occurs. More research is needed on the mechanisms of
behavior change among heavy drinkers across the spectrum of AUD severity.
Research on long-term care management strategies, like those used for other
chronic disorders, is promising, especially for people with severe AUD and
serious mental or physical disorders. For example, studies of heavy drinkers with
severe medical complications such as liver cirrhosis suggest that addressing
drinking using a care management approach in the context of general medical
care is effective at reducing drinking and inducing abstinence (117). In two
studies of this approach, 2-year mortality was about two-thirds of that in
comparison groups receiving usual medical care (118,119). Integrating substance
use interventions into community support programs for severely mentally ill
people also has some support. These studies suggest that for harmful drinkers
with serious medical or psychiatric illnesses, addressing drinking directly in the
context of medical or psychiatric treatment is preferable to referral to a standard
addiction treatment program, which are not often staffed to be able to address
serious medical or psychiatric illnesses. There are no treatment approaches
shown to be effective with severe and persistent AUD in the absence of
comorbidities that cause serious dysfunction. Since this group with severe AUD
is frequently heavy consumers of healthcare, social, and criminal justice
services, development of more effective treatments is a priority. It may be that
external motivating factors, such as skillful application of legal coercion or
contingency management may be effective with this group, especially when
combined with “wrap-around” services that integrate addiction, psychiatric and
medical care as well as social services and sober housing. What is clear is that
treatment for these individuals needs to be structured with the goal of providing
services intermittently or continuously for years to decades rather than weeks or
months.
To summarize, recent research has shown that drinking and associated
symptoms and problems occur along a continuum ranging from none to mild,
moderate, and severe. A large majority of US adults abstains or drinks at lower-
risk levels. Many at-risk drinkers are without current symptoms or problems but
are at increased risk for physical, mental, and substance use disorders developing
over time. In contrast to popular belief, most people who meet AUD criteria do
not have a chronic course and most recover without professional treatment or
even attendance at mutual help groups (43). It appears that most people, upon
recognizing a problem, attempt to change alone or with informal help, and the
majority are eventually successful, albeit after several years of active disorder.
Seeking help from mutual help groups or nonaddiction professionals (about
25%) and/or professional treatment programs (10%) occurs when informal
attempts to change fail or an external contingency is applied, such as a legal
charge for driving while intoxicated or family demands. A significant proportion
of treatment-seekers respond with improvement or remission, although this often
takes years, with multiple quit attempts and recurrences prior to achieve stable
remission. There is a small but important group with severe and persistent AUD.
This continuum of drinking and associated symptoms and problems suggests a
corresponding continuum of care.
Unfortunately, most of this continuum of care is not yet implemented or
available. The quality of care for at-risk drinking and AUD in primary care is the
lowest among thirty chronic conditions (120), and attempts to increase screening
and brief intervention for at-risk drinking have met with little success despite a
robust evidence base for their efficacy (2,110). Among people with a severe use
disorder, the proportion of people receiving treatment increased from 24% to
34% between 2001-2002 and 2012-2013 (13,46), but the prevalence or public
health burden of at-risk drinking or AUD also increased (16). Thus, much
remains to be done and many challenges lie ahead. Nevertheless, this fuller
understanding of the spectrum of drinking, disorders, and treatment approaches
provides one possible conceptual framework for advancing investment and
development of the continuum of care.
A major public health challenge is to provide earlier identification and
appropriate treatment to a much broader spectrum of individuals with unhealthy
alcohol use than is currently the case. There is a pressing need to identify early
intervention strategies for youth who begin drinking in early adolescence and
who are at high risk for later development of severe chronic AUD. Early
identification and treatment of at-risk drinking and AUD in primary care and
general mental health care would provide access for millions of people who
otherwise will not receive treatment. Needed also is a better understanding of the
factors driving change in heavy drinkers and how to facilitate that change both in
addiction treatment and in other settings. Finally, effective and cost-effective
care management strategies for managing chronic severe dependence need to be
implemented. To provide this type of comprehensive care, the specialty
addiction treatment sector will require substantial development so that addiction,
psychiatric, medical, and social services can be provided in an integrated way
over longer periods of time.
TREATMENT AND BEHAVIOR CHANGE

The outcome of treatment varies based on the diagnostic severity, or stage of
illness. In a typical treatment study, about one-third of subjects will be in full
abstinent or nonabstinent remission for the following year, 30%-40% will show
substantial improvement but will have at least some episodes of heavy drinking,
and 20%-30% will not show an effect (99,107,115). However, over the course of
the ensuing 5-10 years, most will suffer at least some recurrences (121). Detailed
information about each different behavioral and pharmacological modality is
provided in the appropriate chapters of this textbook. However, no one technique
has proved to be overall more effective than others, thus raising the question of
what the mechanisms of change really are. In fact, many people start reducing
their drinking prior to treatment entry, and both study protocols and treatment
programs require that someone be abstinent at treatment entry. For that matter,
there are no clear criteria for distinguishing “still drinking” from “abstinent,”
since treatment cannot take place if an individual is intoxicated. In other words,
it is arbitrary how long abstinence is required to qualify as “abstinent.” Even
most daily or near daily drinkers will have a negative blood alcohol level at
some point each day. One could thus conceptualize the start of drinking each day
as a “relapse.” In yet another randomized controlled trial of two behavioral
treatments for AUD that showed no difference between brief motivational
counseling versus a more extensive multimodal program of care, Orford and
colleagues qualitatively examined the process leading to help seeking in study
subjects (122). They identified a “catalyst system” consisting of increasing
problems and distress related to drinking, pressure from others, and a trigger
event, which in turn led to the realization “I cannot do this on my own.” Factors
outside the treatment context continued to be important throughout the recovery
process, especially after the discontinuation of treatment services. In another
study of fifteen community treatment programs, 5-year outcomes of patients
who dropped out of treatment early did not differ from program completers
(123). These findings suggest that the process of deciding to seek help is itself
part of the change process and is arguably the most important, although it is not
well understood.
Treatment seeking is strongly associated with increased odds of achieving
full remission, but help seekers differ systematically from non–help seekers.
Help seekers on average are older and have more severe AUD and more
coexisting mental and physical disorders as well as less social support (64,124).
They are more likely to have severe chronic AUD (46). For those who do seek
help, both professional treatment and 12-step support group participation are
associated with increased likelihood of full remission, especially abstinent
remission (43). For individuals older than 35 years, abstinence is a much more
stable outcome than even light drinking without problems (37,123), while in
younger persons, lower-risk drinking without problems (nonabstinent remission)
is similar to abstinence in predicting continued remission 3 years later (37).
Thus, remission, whether abstinent or nonabstinent, should be the goal of
treatment for AUD, tempered with the recognition that full remission cannot
always be achieved or sustained.
Unfortunately, such studies are not able to establish causality. Although help
seeking and participation in treatment and Twelve Step community support
groups are associated with improved outcomes, including decreased mortality, it
is just as likely out that people who have decided to change will seek treatment,
while those who do not want to change do not, or that people who respond to
treatment early develop more hope and motivation to continue. That is, treatment
participation or continuation may be a result of change rather than the converse.
There may be other unmeasured differences between the groups, as well.
Regardless, people who achieve full remission of AUD have much better overall
functional and medical outcomes that those with partial or no response.
Furthermore, it appears that treatment followed by Twelve Step support group
participation is a frequent and effective (but not the only) path to recovery for
many people (43). Rudolf Moos has emphasized the importance of personal and
social resources to the achievement of remission (125). Specific theories and
treatment components he identifies include social control theory (support, goal
direction, and structure), behavioral economics and behavioral choice theory (an
emphasis on rewards that compete with substance use), social learning theory
(focus on abstinence-oriented norms and models), and stress and coping theory
(attempts to develop self-efficacy and coping skills). Conceptualizations such as
this provide guidance for both research and clinical practice and are particularly
helpful to approach the relationship of factors at different levels of analysis
(neurobiological, personal, and social). This type of integrative thinking and
research will become increasingly important as determinants of change are
further explored. As an indication of this trend, the NIAAA has undertaken a
major research initiative to promote interdisciplinary research into mechanisms
of behavior change related to initiation of positive change among people with
unhealthy alcohol use, and the National Institutes of Health has a similar
initiative to understand health behavior change across a wide variety of disorders
(126,127).
SYSTEMS OF CARE
An ongoing opportunity within the field of addiction medicine is how and where
tailored treatments should be provided to catalyze behavior change. Historically,
rehabilitation programs independent of the healthcare system (n ≅ 13,000) have
been the cornerstone of care for people with alcohol or other substance use
disorders (128). About two-thirds of these programs are publicly funded, relying
primarily on government block grants and state contracts to provide services
(129–131). The remaining privately funded programs largely depend on
revenues from private insurance and self-paying patients (132,133). Most people
with AUD are treated in the publicly funded treatment sector (134,135).
Federal legislative changes have had substantial impacts on the funding and
structure of both publicly and privately funded treatment programs. In 2008, the
Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity
Act (MHPAEA) required Medicaid managed care organizations to provide
coverage benefits for mental health and substance use comparable to those
offered for physical medical services, if they were offered at all. The passage of
the Affordable Care Act (ACA) in 2010 extended these coverage requirements to
commercial health plans and Medicaid’s Alternative Benefit Plans (ABPs).
Coverage of substance use disorder treatment for people enrolled in traditional
Medicaid fee-for-service plans remains at each state’s discretion (136). It is
important to note that future coverage requirements are uncertain given current
Congressional debates regarding the future of the ACA and other potential
changes in the structure of healthcare law. Unfortunately, people with AUD are
unusually vulnerable to changes in health law and policy.
Expansions in coverage stimulated by legislative efforts to date have offered
opportunities for growth and collaboration in addiction treatment delivery. The
ACA incentivized novel approaches to organizing and financing health care that
coordinated primary care and behavioral health services (137). Most traditional
substance use treatment programs have not been able to take advantage of these
innovations, though. The ACA and subsequent laws (ie, Medicare Access and
CHIP Reauthorization Act [MACRA]) require healthcare providers to report on
a variety of metrics to receive Medicare reimbursement without penalty, such as
the use of electronic health records, computerized order entry, and
documentation of quality assurance and improvement efforts. Most states have
similar requirements for Medicaid reimbursement. Many addiction treatment
programs do not have the infrastructure to satisfy such regulatory demands or
bill insurers for their services, so will need significant investments in
information technology and medical services, or collaborative partnerships with
health systems, to provide the highest quality care (7,8,137–139).
State authorities significantly influence the organization and structure of
community treatment programs. Each state, and the District of Columbia, has a
single state authority (SSA) funded by both federal and state monies that is
charged with overseeing substance use treatment programs. SSAs contract with
or license almost all programs—either directly or indirectly through counties and
other organizations—to ensure service delivery. In their regulatory and funding
roles, SSAs play a major role determining how evidence-based practices and
patient values are integrated into treatment programs (140,141). Although most
SSAs provide technical assistance to foster collaborations between publicly
funded addiction treatment programs, mental health programs, and the criminal
justice system, about 40% of the agencies do not provide support to facilitate
collaborations with medical programs or federally qualified health centers (137).
Despite growing evidence demonstrating the importance of medications and
healthcare services to recovery, only 15% of substance use treatment programs
have contracts with accountable care organizations and these are largely for out-
of-network referrals (142). As federal healthcare reform evolves, SSAs will be
challenged to transition the treatment of substance use disorders into more
medically oriented settings (143,144).
Most care for AUD occurs in programs where it is uncertain whether a
medical professional would be involved in their care, despite legislative and
reimbursement efforts to promoting a medical model of care. In 2002–2004, only
30.7% of publicly funded programs had a physician on staff compared with
50.7% of privately funded programs, whereas a slightly higher percentage of
publicly funded programs (35.4%) employed a physician on contract compared
with private programs (26.1%) (7). Average utilization of medical staff by
substance use disorder treatment programs increased by 26% from 2007 to 2010,
a trend encouraged by the implementation of the ACA (145). However, uptake of
medication treatment remains very low. The most strongly endorsed barriers to
use of antirelapse medications were regulatory prohibitions due to the program’s
lack of medical staff, funding barriers to implementation, and lack of access to
medical personnel with expertise in prescribing antirelapse medications (146).
The lack of physicians and other advanced practice providers familiar with both
pharmacological and psychotherapeutic treatment modalities for AUD, even
among those working for treatment programs, is a formidable barrier to quality
care. This limitation is accentuated by the time-limited care standard to most
treatment programs, whereby patients are often discharged to follow-up with
providers unfamiliar with how to support recovery, if they are discharged to
follow up with healthcare providers at all.
Changes in health care’s regulatory and financial environment, as well as an
increased recognition of the impact medications can have on alcohol use, have
made efforts to address unhealthy alcohol use in primary care more appealing.
Accountable care organizations (ACOs) and similarly structured capitated
managed care organizations must focus on population health to be financially
sustainable. Increased healthcare costs may be attributable to unhealthy alcohol
and other substance use both at the individual (147,148) and family levels
(68,149–151). Efforts to integrate screening and interventions for alcohol have
focused on primary care with a concomitant increase in screening rates when it
is incorporated into a clinic’s normal work flow (152,153). Corresponding
efforts to increase the provision of brief intervention and referral to treatment
programs have been unsuccessful (154,155). Integrating behavioral health
providers into primary care settings may increase the provision of appropriate
brief interventions, but the integration of behavioral health and primary care
overall remains low (156). Realizing the potential value of screening, brief
intervention, and referral to treatment (SBIRT) has been difficult to achieve in
practice.
Regardless of the use of SBIRT, multiple studies have shown that people
with medical and substance use comorbidities do better with ongoing, high-
quality primary care involvement (157–159). Hence, efforts have evolved to
improve these patients’ health outcomes while reducing overall costs of care.
While studies of providing primary care treatment for individuals with substance
use disorder overall have yielded mixed results, outcomes specific to unhealthy
alcohol use have been more favorable. In Kaiser Northern California, integration
of substance use treatment (not just alcohol) into primary care yielded a slight
increase in costs, but only demonstrated a benefit in use outcomes for patients
with substance-related medical conditions (160). Saitz and colleagues studied the
use of a chronic care management model versus usual primary care with no
change in the rate of abstinence from heavy drinking or health-related quality of
life (161). However, they did find that people with AUD had fewer alcohol
problems even if they had comorbid major depression or PTSD (161,162).
Within the VA, Oslin and colleagues found delivering pharmacotherapy and
psychosocial support for alcohol dependence in a primary care setting, compared
to a specialty addiction clinic, resulted in a significantly higher proportion of
participants engaged in treatment over 26 weeks, and a significantly lower
percentage of heavy drinking days without any difference in the rate of
abstinence between groups (163). Embedding addiction specialists in high-risk
clinical settings for rapid referral also produced significant improvements in
medical and alcohol use outcomes (164). Thus, managing unhealthy alcohol use
within a primary care relationship—referring to specialists when necessary—
improves the likelihood of remission (165). More information on models of care
integration, challenges posed, and implications for patients seeking care for
substance use disorders are discussed in Chapter 29 of this textbook.
INTEGRATING THE EVIDENCE AND

PERSONALIZING PRACTICE
Given the proliferation of new research, it is a challenge to understand and
incorporate new findings into practice. Unfortunately, although studies of the
efficacy of various treatments may help determine how one treatment compares
to another treatment or to no treatment, there are few studies that directly address
questions of central importance to clinicians. For example, should one
recommend a few sessions of motivational enhancement therapy or an intensive
day program for the treatment of AUD? If a person with at-risk drinking does
not respond to brief motivational counseling, what is the appropriate next step?
Is the stepped care strategy, where the least restrictive and expensive option for a
situation is offered first, the best approach? How much evidence is required
before recommending a new treatment? How much evidence is required before
failure to offer or recommend a treatment based on personal taste or ideology is
ethically indefensible?
Although it is not possible to provide definitive answers for these questions,
certain conclusions emerge from available evidence. Although there is no
systematic advantage of type of behavioral therapy to another, the quality of the
behavioral treatment provided is important. Specifically, empathic, skillful
therapy is more effective than confrontation and education. Furthermore, it is
more important to engage someone with AUD in treatment than which treatment
is used. Therefore, it makes sense to offer a variety of treatment options, since
patients are likely to vary in their preferences. The same holds true for the
setting of treatment. Unless someone is unable to abstain living in the
community, there is no advantage of residential versus outpatient treatment, or of
intensive versus less intensive outpatient treatment. Second, antirelapse
medications offer clinically important benefit in early recovery and therefore
patients should routinely be made aware of them and offered the opportunity to
use them. Current evidence provides no guidance, however, on choosing one
medication over another, or what the sequence of subsequent antirelapse
medications should be. For appropriate patients (mild to moderate levels of
AUD, little or no coexisting psychopathology, socially stable, and motivated to
change drinking), medication with medical care management and
encouragement to abstain, adhere to treatment, and attend community support
groups is as effective as specialized alcohol counseling. Third, a social network
supportive of abstinence is at least as important as whatever treatment occurs in
determining outcome (166). Except for referral to community support groups,
this aspect of treatment tends to be neglected, to the detriment of our patients.
Behavioral marital therapy, for example, has a strong evidence base (167).
Finally, for any given diagnosis (eg, at-risk drinking vs. AUD), there is not yet a
way to identify patient characteristics that reliably predict differential response
to different treatments, although research in this area is promising.
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CHAPTER 28
The Treatment of Addiction: An
Overview
Andrea G. Barthwell, Lawrence S. Brown Jr., and Megan
E. Crants
CHAPTER OUTLINE
Introduction
Goals of Addiction Treatment
Treatment Settings
Residential Programs, Including Therapeutic Community
Treatment Services
Pharmacological Therapies
Conclusion
INTRODUCTION
Addiction is a complex illness. Compulsive (at times uncontrollable) drug
seeking and use, which persist even in the face of extremely negative
consequences, characterize the disorder. For many patients, addiction is a
chronic disease, with relapses possible even after long periods of abstinence.
Patients with substance use disorders are heterogeneous in a number of clinically
important features and domains. Because addiction has so many dimensions and
disrupts so many aspects of an individual’s life, treatment for this illness never is
simple; generally, a multimodal approach to treatment is required. Drug
treatment must help the individual stop using drugs and maintain a drug-free
lifestyle while achieving productive functioning in the family, at work, and in
society. After repeated failures of appropriately matched treatment, some
individuals are deemed unable to stop using drugs. In this instance, it is
appropriate to work to achieve intermediate outcomes that include a reduction in
the use and effects of substances, reduction in frequency and severity of relapse
to substance use, and improvement in psychological and social functioning.
Physicians are cautioned that the latter is hard to achieve with continued drug
use.
Effective treatment programs typically incorporate many components, each
directed to a particular aspect of the illness and its consequences. In practice,
specific pharmacological and psychosocial treatments are often combined
because combined treatments lead to better treatment retention and outcomes
(1). Three decades of scientific research and clinical practice have yielded a
variety of approaches to addiction treatment; the most effective approaches
match the patient’s assessed needs to services that, research suggests, might have
the most impact. Evidence suggests that individuals with substance use disorders
who achieve sustained abstinence have the best long-term outcomes (2,3).
Extensive data show that such treatment is as effective as treatment for most
other chronic medical conditions (4). Of course, not all addiction treatment is
equally effective or applied in a standardized way. Research also has revealed a
set of overarching principles that characterize the most effective addiction
treatments and their implementation (Table 28-1).
TABLE 28-1 Principles of Effective Treatment

Adapted from National Institute on Drug Abuse. Principles of Drug Addiction Treatment: A Research-
based Guide. 3rd ed. Rockville, MD: NIDA (NIH Publication No. 12–4180), 1999:2-5.
GOALS OF ADDICTION TREATMENT

Addiction is a complex disorder that can involve virtually every aspect of an
individual’s functioning—in the family, at work, and in the community. Because
of addiction’s complexity and pervasive consequences, addiction treatment
typically must involve many components. Some of those components focus
directly on the individual’s drug use, whereas others, such as employment
training, focus on restoring the addicted individual to productive membership in
the family and society (Fig. 28-1). Treatment of addiction is delivered in many
different settings, using a variety of behavioral and pharmacological approaches.
In the United States, more than 11 000 specialized drug treatment facilities
provide rehabilitation, counseling, behavioral therapy, medication, case
management, and other types of services to persons with substance use and
gambling disorders.
Figure 28-1 Components of addiction treatment. (From
National Institute on Drug Abuse. Principles of Drug
Addiction Treatment— A Research-based Guide. 3rd ed.
Rockville, MD: NIDA. NIH Publication No. 12–4180, 2012.)
Care of individuals with substance use disorders includes assessing needs,

providing treatment for intoxication and withdrawal, and developing, with
appropriate support, the treatment plan that may consist of referrals to
psychosocial care or referrals for co-occurring medical disorders. The treatment
plan should address how the patient will achieve abstinence without medical
compromise, achieve and maintain abstinence after withdrawal (if indicated),
and gain improvement in functioning in the medical, social, and psychological
domains.
TREATMENT SETTINGS
Historically, the addiction treatment delivery system was primarily a specialty
care delivery system, often separate from the medical–surgical delivery system.
Funding for care in the system is usually separate, and the professionals in the
system are different. Treatment settings vary widely with regard to services and
medical support available and the milieu or philosophy. For physicians,
assessment for treatment matching and knowledge of referral and funding
options in the community are important, as every community is different.
Much of the foregoing must be considered in the context of fundamental
changes over the past decade. Federal parity legislation and the Affordable Care
Act have provided care through expanded use of Medicaid funding.
Additionally, bipartisan approval, signed by President Obama, led to the passage
of the Comprehensive Addiction and Recovery Act (CARA) of 2016 (5),
expanding access to addiction treatment and permitting midlevel providers to
prescribe buprenorphine, following required training.
However, there are at least two major impediments, one in the present and
one potentially in the future. The first is that despite permissive federal
legislation, health care, including addiction services, is ultimately decided by the
states. Accordingly, many states have not expanded the use of Medicaid funding
to improve access to addiction treatment. The role of the states is also critical
regarding the 2016 CARA as the participation by midlevel providers is
contingent upon authorization by states to permit this change in their scope of
practice. Also, any changes to the Affordable Care Act may decrease access to
Medicaid-reimbursed services, including addiction care.
While this chapter addresses treatment for all substances, it is important to
recognize that the utilization and capacity of treatment vary by setting. For
instance, substantially more patients receive opioid agonist medication treatment
with buprenorphine than patients receiving methadone in opioid treatment
programs. Yet, both of these settings do not adequately approach the need for
opioid agonist treatment (6). Decisions regarding the site of care should be based
on the patient’s ability to adhere with and benefit from the treatment offered, to
refrain from use of substances, and to avoid high-risk behaviors, as well as the
patient’s need for structure and support or particular treatments that may be
available only in certain settings. Patients can move from one level of care to
another based on these factors and an assessment of their ability to benefit from
a different level of care. Delivery system discontinuities occur when coverage is
available for a limited number of levels of care, but not the one indicated based
on the assessment carried out using a standardized system such as the American
Society of Addiction Medicine (ASAM) Criteria. The ASAM Criteria (Chapter
30) describes four levels of care: (a) outpatient services, (b) intensive
outpatient/partial hospitalization services, (c) residential/inpatient services, and
(d) medically managed intensive inpatient services. An addiction medicine
consultant or a member of the medical staff who is knowledgeable in the
diagnosis and treatment of addiction can make criterion-based placement.
Sometimes, the payer will insist that external case managers employed by the
payer should make criterion-based decisions. In some instances, placement
decisions are not criteria based.
Hospital-based physicians may find their management of addiction limited to
withdrawal management and referral. It is uncommon to refer outside of the
hospital, because either the payer requires referral to a contracted provider or the
patient lacks coverage and needs referral to the public system of care. Hospital-
based physicians can create an inpatient Addiction Medicine Consultation
Service with specialty-trained clinicians and nonphysician clinicians who assess
addiction severity and withdrawal potential, manage withdrawal, and refer to
posthospital addiction care when the patient no longer requires care in the
hospital setting.
Withdrawal Management
According to the ASAM Criteria, withdrawal management refers not only to the
attenuation of the physiological and psychological features of withdrawal
syndromes but also to the process of interrupting the momentum of compulsive
use in persons diagnosed with substance use disorder (7). Because withdrawal
management is not an adequate approach to addressing a substance use disorder
as a stand-alone level of care, it must be conceived as an entry point into
treatment, not a separate level of care. This phase frequently requires a great
intensity of services to establish treatment engagement and patient role
induction. It may be delivered in ambulatory settings with and without extended
on-site monitoring. In residential or inpatient settings, it is delivered under
clinically managed, medically monitored, or medically managed conditions.
There is increasing intensity of services and involvement of nursing and medical
personnel across the latter continuum.
Hospital Settings
Hospitalization is appropriate for patients whose assessed need cannot be treated
safely in an outpatient or emergency department setting because of (a) acute
intoxication, (b) severe or medically complicated withdrawal potential, (c) co-
occurring medical or psychiatric conditions that complicate withdrawal
management or impair treatment engagement and response, (d) failure of
engagement in treatment at a lower level of care, (e) life- or limb-threatening
medical conditions that would require hospitalization, (f) psychiatric disorders
that make the patient an imminent threat to self or others, and (h) failure to
respond to care at any level such that the patient endangers others or poses a
self-threat. Aside from withdrawal management and management of overdose or
intoxication, most patients are receiving services incident to a medical–surgical
need to manage a biomedical condition or complication or a psychiatric need to
manage an emotional or behavioral condition in a primary psychiatric setting.
The physician must evaluate the timing and intensity of addiction medicine
services in the context of other concerns.
Outpatient Programs
This treatment varies in the types and intensity of services offered, ranging from
specialty programs to individual physician offices and primary care settings. It
costs less than residential or inpatient treatment and often is more suitable for
individuals whose ASAM Criteria show insight into his or her disease, a high
degree of predicted compliance, low symptomatology, high resource availability
and use, and a supportive structure in his or her home environment. Low-
intensity programs may offer little more than education and encouragement and
support; however, as in the other treatment settings, a comprehensive approach is
optimal, using—where indicated—a variety of psychotherapeutic and
pharmacological interventions along with behavioral monitoring. High rates of
attrition can be problematic, particularly in the early phase. Because outcomes
are highly correlated with time in treatment, retention should be one focus of
treatment, along with self-efficacy regarding adherence to the abstinence plan.
Self-help participation is useful (8).
Other outpatient models, such as intensive day treatment, can be comparable
to residential programs (see below “Residential Programs, Including Therapeutic
Community”) in services and effectiveness, depending on the individual
patient’s characteristics and needs. In many outpatient programs, as in much of
treatment in general, group counseling is emphasized. Some outpatient programs
are designed to treat patients who have medical or mental health problems in
addition to their substance use or gambling disorder (9).
Most alcohol use disorders are treated outside of the hospital after medical
complications associated with withdrawal management are addressed (10,11).
Similarly, cocaine (12), nicotine (13), and marijuana use disorders are treated on
an outpatient basis as long as the focus on reduced substance use can be
maintained and there are no other reasons for hospitalization (14,15).
Partial Hospital Programs and Intensive
Outpatient
Partial hospitalization is considered for patients who require intensive care but
have a reasonable chance of making progress on treatment goals in the
intertreatment interval, including maintenance of abstinence. It is often provided
to individuals whose treatment is hospital or residential initiated and who still
require frequent and concentrated contact with treatment professionals to
monitor their behavior and manage their risk of relapse. These patients often
have a history of relapse after completion of treatment or are returning to a high-
risk environment and have a need to develop support for their recovery-focused
efforts beyond the treatment system. Lack of motivation to continue to build on
the gains made in the treatment, allowing the treatment effect to erode, is often a
cause to continue the patient in this highly intensive and structured setting.
Intensive outpatient programs have been proven to be effective when working
with special subgroups of patients, such as those who are economically
disadvantaged, psychiatrically compromised, and pregnant or who have been
coerced into treatment by the criminal justice system or outside parties (6). The
difference between partial hospital programs and intensive outpatient is seen in
intensity, number of hours per day, setting of the program, and structure of the
program. Patients who are not successful in intensive outpatient may have
clinical contact increased by transfer to partial hospital programs.
RESIDENTIAL PROGRAMS, INCLUDING

THERAPEUTIC COMMUNITY
Residential programs provide care 24 hours a day, generally in nonhospital
settings. Residential care is generally provided to patients who do not meet the
clinical criteria for hospitalization but whose lives are transformed by and
focused on substance use. These individuals are unlikely to maintain abstinence
in the absence of continued application of a variety of therapeutic techniques in a
highly structured and supportive environment. Short-term programs provide
intensive but relatively brief residential treatment based on a modified 12-step
approach and may or may not include elements of therapeutic communities
(TCs) (see the following paragraph). The duration of residential treatment should
be determined by the clinical response to therapy and the length of time
necessary for the patient to meet specific criteria predictive of success in a lower
level of care according to the ASAM Criteria. The relationship between length
of treatment and clinical outcomes is mixed, largely due to differences in study
designs (16,17). These programs originally were designed to treat alcohol
problems, but during the cocaine epidemic of the mid-1980s, many began to
treat other substance use disorders. The original residential treatment model
consisted of a 3- to 6-week hospital-based inpatient treatment phase, followed by
extended outpatient therapy and participation in a self-help group such as
Alcoholics Anonymous. Reduced healthcare coverage for addiction treatment
has resulted in a diminished number of these programs, and the average length of
stay under managed care review is much shorter than in early programs (18).
One residential treatment model is the therapeutic community (TC), but
residential treatment programs also employ other models, such as cognitive–
behavioral therapy. Note that these are different from “sober houses,” which may
not be accredited or provide evidence-based treatment. TCs are residential
programs with planned lengths of stay from 6 to 12 months. TCs focus on the
“resocialization” of the individual and use the program’s entire “community”—
including other residents, staff, and the social context—as active components of
treatment. Addiction is viewed in the context of an individual’s social and
psychological deficits, so treatment focuses on developing personal
accountability and responsibility and socially productive lives. Treatment is
highly structured and can at times be confrontational, with activities designed to
help residents examine damaging beliefs, self-concepts, and patterns of behavior
and to adopt new, more harmonious and constructive ways to interact with
others. Many TCs are quite comprehensive and include employment training and
other support services on-site or through formal linkage agreements. Compared
with patients in other forms of drug treatment, the typical TC resident has more
chronicity and criminal involvement. Research shows that TCs can be modified
to treat individuals with special needs, including adolescents, women (19,20),
those with severe mental disorders (21), and individuals in the criminal justice
system. Recently, with pressure from reimbursement sources, the elements of
TCs have been incorporated into shorter-term residential programs and
institutional criminal justice settings.
Heroin addiction has been effectively reduced in the TC; however, return to
use rates after TC treatment is higher than 80% in most long-term follow-up
studies, indicating a need for selectivity in application of this modality over
clinical settings that provide medication (22). Data regarding the effectiveness of
traditional long-term TC are limited by the low completion rates of 15%-25%,
with most attrition occurring during the first 3 months. Retention lengths predict
outcomes on abstinence with abstinence success rates of 90% for graduates of 2-
year programs and 25% for dropouts of the same programs completing <1 year
(23). Retention rates differ with program sites (24,25).
Community Residential Rehabilitation

Community residential rehabilitation facilities include “halfway houses” or
“sober living facilities,” with the former providing more structure and
supervision. Individuals referred to these settings are generally deemed to be at
risk for relapse without such support. Often, this setting is offered to the
individual whose environmental risk is great or those needing a number of
services after primary treatment to address deficits in vocation, employment, and
social supports. These services have been shown to significantly improve
substance use outcomes for both sexes but are variable in their impact on young
people (26,27). That being said, there is wide variability in the quality of these
programs, as some facilities lack licensure or accreditation.
Case Management
Case management is a collaborative process that assesses, plans, implements,
coordinates, monitors, and evaluates the options and services to meet an
individual’s health needs (28–30). It uses communication and available resources
to promote quality, cost-effective outcomes.
Case management, although difficult to assess for effectiveness in a rigorous
fashion, has been shown to be an effective adjunctive treatment for patients with
alcohol use disorders, patients with substance use disorders co-occurring with
psychiatric disorders (31), and adolescents (32). Case management is provided to
individuals whose social situation and complex needs would impair their ability
to adhere to a prescribed treatment plan and follow-up care. Basic needs are
often met as part of the service array, which includes as psychoeducation and
assistance in comprehension of the extent and nature of the disease for which
treatment is provided and advocated.
Aftercare Programs
Aftercare generally follows an episode of care and is focused on maintenance of
gains made in treatment over a prescribed period with less frequent contact than
the primary episode of care (eg, once-weekly monitoring and group therapy after
a 6-week intensive outpatient program in which the patient is seen nightly for 3
hours). The patient’s affiliation with a 12-step program is encouraged, and the
transition to self-efficacy is monitored. Many professionals view the term
“aftercare” as outdated, in that it suggests that care has somehow ended. As
such, some prefer the use of the term “outpatient addiction rehabilitation
treatment” or follow-up.
Sober Coaches, Recovery Coaches, and Other

Support Services
Sober coaches, recovery coaches, and other such aides provide nonprofessional
supervision and guidance to individuals going through the recovery process.
They are meant to encourage healthy structures and rituals, as well as offer
specific suggestions on a new way of living and behaving. The Medication-
Assisted Recovery Support (MARS) project, sponsored by the National Alliance
for Medication-Assisted (NAMA), is a prominent agency promoting recovery,
especially for patients during and following medication treatment. Aides may
also be able to help their clients build responsibility and develop an improved
sense of judgment as well. These coaches are best used in combination with a
comprehensive treatment plan that addresses the multifaceted needs of
individuals in recovery. Ideally in the future, professionals will be able to offer
sustainable, adaptable treatment programs that provide the type of services these
aides offer while negating the necessity of nonprofessional guidance. Until then,
these aides offer a temporary solution for working the remedy, especially during
early recovery (33).
Treatment in the Physician’s Office, Including

Screening and Brief Interventions
The addiction treatment enterprise has traditionally been separate and distinct
from addiction medicine, with addiction medicine provided in the context of
addiction treatment in sometimes limited ways. Public policies, practices, and
laws have worked against the provision of care by physicians for the addicted
individual. For example, the Harrison Narcotics Tax Act of 1914 was a US
federal law that regulated and taxed the production, importation, and distribution
of opioids. The courts interpreted this to mean that physicians could prescribe
narcotics to patients in the course of normal treatment but not for the treatment
of addiction. Despite long-standing barriers to care and the risk of prosecution,
physicians have recognized a need to provide care to addicted individuals.
Medications are also available for office-based treatment of other substance use
and gambling disorders.
Brief interventions for at-risk drinking had been studied before being
adopted and expanded for substance use disorders (34). Interventions were
intended to facilitate reduction of at-risk drinking in settings other than those in
the addiction treatment enterprise (eg, mental health clinics, physician’s offices)
(35,36).
Brief interventions include assessment, feedback, responsibility for change,
advice, and menu of options provided using empathic listening and encouraged
self-efficacy (37). A more extensive review of this area is offered elsewhere in
this textbook.
Criminal Justice Settings for Mandated

Treatment, Including Drug Courts
Research has shown that combining criminal justice sanctions with drug
treatment can be effective in decreasing drug use and related crime. Individuals
under legal coercion tend to stay in treatment for a longer period and do as well
as or better than others not under legal pressure (38). Often, persons with
substance use disorders encounter the criminal justice system earlier than other
health or social systems, and intervention by the criminal justice system to
engage the individual in treatment may help to interrupt and shorten a lifetime of
drug use (39,40). Addiction treatment may be delivered before, during, after, or
in lieu of incarceration.
Prison-Based Treatment Programs

Incarcerated individuals with substance use disorders may encounter a number
of treatment options, including opioid agonist treatment (41), while incarcerated,
as well as didactic drug education classes, self-help programs, and treatment
based on TC or residential milieu therapy models. The TC model has been
studied extensively and found to be quite effective in reducing drug use and
recidivism to criminal behavior (42). Those in treatment are generally segregated
from the general prison population, so that the “prison culture” does not
overwhelm progress toward recovery. As might be expected, treatment gains can
be lost if inmates are returned to the general prison population after treatment.
Research shows that relapse to substance use and return to crime are
significantly lower if the incarcerated individual with a substance use disorder
continues treatment after returning to the community (43,44).
Community-Based Treatment for Criminal

Justice Populations
Several criminal justice alternatives to incarceration have been tried with
offenders who have substance use disorders, including limited diversion
programs, pretrial release conditional on entry into treatment, and conditional
probation with sanctions. The drug court is a promising approach. Drug courts
mandate and arrange for drug addiction treatment, actively monitor progress in
treatment, and arrange other services for drug-involved offenders. Federal
support for planning, implementation, and enhancement of drug courts are
provided under the U.S. Department of Justice’s Drug Courts Program Office.
As a well-studied example, the Treatment Accountability for Safer Communities
program provides an alternative to incarceration by addressing the multiple
needs of drug addicted offenders in a community-based setting (45). Treatment
Accountability for Safer Communities programs typically include counseling,
medical care, parenting instruction, family counseling, school and job training,
and legal and employment services. The key features of Treatment
Accountability for Safer Communities include coordination of criminal justice
and drug treatment; early identification, assessment, and referral of drug-
involved offenders; monitoring offenders through drug testing; and use of legal
sanctions as inducements to remain in treatment.
TREATMENT SERVICES
This section presents several examples of evidence-based treatment approaches
and components that have been developed and tested through research supported
by the National Institute on Drug Abuse. Each approach is designed to address
certain aspects of drug addiction and their consequences for the individual,
family, and society. These approaches are best used to enhance and standardize
the quality of best practices in existing treatment programs. This section is not a
complete list of empirically supported treatment approaches. Additional
approaches are under development as part of National Institute on Drug Abuse’s
continuing support of treatment research and are reviewed in this section, as well
as other sections of this textbook.
Somatic services are defined as those used to manage intoxication,
withdrawal syndromes, and pathophysiological effects and other clinical
manifestations of the substance used. Medications are provided in conjunction
with behavioral therapies and self-help involvement. Behavioral therapies and
medications are provided in a number of settings, including hospitals and by
hospitalists and other primary care specialists in office-based settings. These
services are based on scientific advances in the behavioral sciences and
neurobiology of a wide range of drugs, alcohol, tobacco, and other psychoactive
substances. These services are discussed in more detail in Sections 7 and 8 of
this textbook.
Clinical Monitoring
As with the treatment of other medical disorders and irrespective of the
therapeutic approach chosen, clinical monitoring is extremely important in
achieving successful clinical options. Although many studies have underscored
the limitations of relying solely on a patient’s self-report (46), this type of
information is most useful in the context of a nonconfrontational,
nonjudgmental, patient–provider relationship based on openness, understanding,
and empathy. It should also be explicitly recognized that patients receiving care
for other chronic disorders also underreport unhealthy behaviors to their
caregivers, and because substance use is stigmatized and often illegal,
underreporting is understandable as is the expectation that reports be objectively
verified.
Because of the limitations of self-report in the initial assessment and during
clinical monitoring, clinical drug testing represents an important tool for
addiction medicine specialists (47,48) but is underused and often misunderstood
by primary care providers (49,50). When used in concert with a good history,
physical examination, and biomarkers, clinical drug testing facilitates screening,
assessment, diagnosis, and clinical monitoring of a substance use disorder in the
hands of an experienced practitioner. Drug testing provides useful information
about a patient’s potential for achieving desirable clinical outcomes with co-
occurring medical or psychiatric disorders.
Managing Intoxication and Withdrawal

Similar to the treatment of other clinical disorders, patients with substance use
disorders exhibit varied clinical presentations, from acute and subacute to
chronic manifestations. Some manifestations, such as intoxication and
withdrawal, can be life-threatening without appropriate, if not emergent,
intervention. The therapeutic response is contingent on the substance used, the
presence or absence of evidence of a compromised cardiopulmonary system, and
the underlying health status of the patient. Pharmacotherapy is the cornerstone
for patients with either intoxication or withdrawal, although effective treatment
for intoxication typically requires a hospital setting, whereas withdrawal can be
treated in either an inpatient or outpatient setting.
Withdrawal management is a commonly used approach in responding to
patients with clinical signs of intoxication or withdrawal. It is a process in
which, under the care of a physician, individuals are systematically withdrawn
from addicting drugs in an inpatient or outpatient setting. Withdrawal
management is intended to reduce or eliminate the medical consequences of
withdrawal, the pain of withdrawal, or the acute increase in craving experienced
by the patient while establishing a therapeutic alliance with the patient and
enabling the patient’s own motivation toward rehabilitation therapies that follow.
Medications are available for withdrawal management or tapering from opioids,
nicotine, benzodiazepines, alcohol, barbiturates, and other sedatives. Withdrawal
management alone does not address the associated psychological, social, and/or
behavioral problems associated; therefore, this clinical approach does not
typically produce the type of lasting behavioral changes necessary for recovery.
Withdrawal management is most useful when it incorporates formal processes of
assessment and referral to subsequent addiction treatment (51) as relapse rates
are high following withdrawal management alone. It may be better conceived as
early treatment engagement, preceding a full continuum of services.
Therapy
Numerous studies have demonstrated that therapy or counseling can be an
effective treatment for some substance use disorders. They attempt to arrest
compulsive substance use through modification of behaviors, feelings, social
functioning, and thoughts. They address a set of common tasks and attempt to
increase motivation, expand the coping repertoire, change reinforcement
contingencies to increase the frequency of positive behaviors, improve mood,
and enhance interpersonal connection and the number of social supports. Lack of
knowledge regarding how to match patients to the various techniques should not
be an excuse to avoid referral for consideration of addiction-specific
psychotherapies. In fact, such therapies may complement effective
pharmacotherapies (52–54).
Cognitive–Behavioral Therapy
Cognitive–behavioral therapy is based on the theory that learning processes play
a critical role in the development of maladaptive patterns of behavior.
Cognitive–behavioral therapy targets two processes: dysfunctional thoughts and
maladaptive behaviors. Thought-based interventions focus on increasing the
patient’s resolve not to use—based on negative and positive consequences of use
—and confronting thoughts about use. Relapse prevention is an example of
cognitive–behavioral therapy with which physicians might be familiar. Relapse
prevention was developed for the treatment of unhealthy alcohol use and later
adapted to other substance use disorders. Relapse prevention encompasses
several cognitive–behavioral strategies that facilitate abstinence as well as
provide help for persons who experience relapse. The goal of relapse prevention
is to help addicted individuals learn to identify and correct problematic
behaviors. For example, the relapse prevention approach to the treatment of
cocaine use disorders consists of a collection of strategies intended to enhance
self-control (55). Specific techniques include exploring the positive and negative
consequences of continued use, self-monitoring to recognize drug cravings early
on and to identify situations that pose high risk of use, and developing strategies
for coping with and avoiding high-risk situations and the desire to use. A central
element of this treatment is anticipating the problems patients are likely to meet
and helping them develop effective coping strategies. Research indicates that the
skills individuals learn through relapse prevention therapy remain after the
completion of treatment (56). In one study, most persons receiving this
cognitive–behavioral approach maintained the gains they made in the treatment
throughout the year after discharge (57).
Motivational Enhancement Therapy

Motivational enhancement therapy is a patient-centered counseling approach that
attempts to initiate behavior change by helping patients resolve their
ambivalence about engaging in treatment and stopping drug use. This approach
employs strategies to evoke rapid and internally motivated change in the patient,
rather than guiding the patient stepwise through the recovery process. The
therapy provides feedback generated from an initial assessment to stimulate
discussion regarding personal substance use and to elicit self-motivational
statements. Motivational interviewing principles are used to strengthen
motivation and build a plan for change. Coping strategies for high-risk situations
are suggested and discussed with the client. Over time, the therapist monitors
change, reviews cessation strategies being used, and continues to encourage
commitment to change or to sustained abstinence. Patients sometimes are
encouraged to bring a significant other to sessions. This approach was developed
for tobacco use disorder and has been used successfully with individuals with
alcohol and cannabis use disorders (58).
Community Reinforcement Approach Plus

Vouchers
Admittedly, community reinforcement may not necessarily be viewed as
intensive outpatient care, defined as a prescribed number of hours of services
weekly. Community reinforcement approach (CRA) is an outpatient therapy for
the treatment of cocaine (59), alcohol (60), opiate (61), and cannabis use
disorder (62,63). The treatment has dual goals: to achieve abstinence long
enough for patients to learn new life skills that will help sustain abstinence and
to reduce consumption. Patients attend one or two individual counseling sessions
per week, where they focus on improving family relations, learning a variety of
skills to minimize drug use, receiving vocational counseling, and developing
new recreational activities and social networks. Those with unhealthy alcohol
use receive clinic-monitored disulfiram (Antabuse) therapy. Patients submit
urine samples two or three times per week and receive vouchers for negative
samples. The value of the vouchers increases with consecutive negative samples.
Patients may exchange their vouchers for retail goods that are consistent with an
alcohol-free lifestyle. This approach facilitates patients’ engagement in treatment
and systematically aids them in gaining substantial periods of alcohol abstinence
(64). The approach has been tested in urban and rural areas and used
successfully in outpatient withdrawal management of adults with opioid use
disorder and with inner-city patients receiving methadone who have high rates of
intravenous cocaine use (65).
A computer-based version of CRA plus vouchers called the therapeutic
education system was found to be nearly as effective as treatment administered
by a therapist in promoting abstinence from opioids and cocaine among opioid-
dependent individuals in outpatient treatment (66). A version of CRA for
adolescents addresses problem solving, coping, and communication skills and
encourages active participation in positive social and recreational activities
(67,68).
Voucher-Based Reinforcement Therapy in

Methadone Treatment
Voucher-based reinforcement therapy helps patients achieve and maintain
abstinence from substances by providing them with a voucher each time they
provide a drug-free urine sample. The voucher has monetary value and can be
exchanged for goods and services consistent with the goals of treatment.
Initially, the voucher values are low, but their value increases with the number of
consecutive drug-free urine specimens the individual provides. Cocaine- or
heroin-positive urine specimens reset the value of the vouchers to the initial low
value. The contingency of escalating incentives is designed specifically to
reinforce periods of sustained abstinence. Studies show that patients receiving
vouchers for drug-free urine samples achieved significantly more weeks of
abstinence and significantly more weeks of sustained abstinence than patients
who were given vouchers independent of urine toxicology results. In another
study, urine toxicology positive for heroin decreased significantly when the
voucher program was started and increased significantly when the program was
stopped (69).
Day Treatment With Abstinence

Contingencies and Vouchers
This approach was developed to treat crack cocaine addiction among homeless
persons (70). For the first 2 months, participants were required to spend 5.5
hours daily in the program, which provided lunch and transportation to and from
shelters. Interventions included individual assessment and goal setting,
individual and group counseling, multiple psychoeducational groups (eg,
didactic groups on community resources, housing, cocaine, and HIV/AIDS
prevention, establishment and review of personal rehabilitation goals, relapse
prevention, and weekend planning), and patient-governed community meetings,
in which patients reviewed contract goals and provided support and
encouragement to each other. Individual counseling occurs once per week, and
group therapy sessions are held three times per week. After 2 months of day
treatment and at least 2 weeks of abstinence, participants graduate to a 4-month
work component that pays wages, which can be used to rent inexpensive, drug-
free housing. A voucher system also rewards drug-free social and recreational
activities. This innovative day treatment was compared with treatment consisting
of twice-weekly individual counseling and 12-step groups, medical examinations
and treatment, and referral to community resources for housing and vocational
services. Innovative day treatment followed by work and housing (dependent on
drug abstinence) had a more positive effect on alcohol use, cocaine use, and days
of homelessness (71).
Individual Psychotherapies
Individualized counseling focuses directly on reducing or stopping the patient’s
substance use. It also addresses related areas of impaired functioning—such as
employment status, illegal activity, and family/social relations—as well as the
content and structure of the patient’s recovery program. Through its emphasis on
short-term behavioral goals, individualized drug counseling helps the patient
develop coping strategies and tools for abstaining from drug use and then
maintaining abstinence. This can be achieved with and without formal
psychotherapy. The licensed provider trained in such therapy encourages 12-step
program participation and makes referrals for needed supplemental medical,
psychiatric, employment, and other services. Individuals are encouraged to
attend sessions one or two times per week. In a study that compared patients
with DSM-IV–defined opioid use disorder receiving methadone alone with those
receiving methadone coupled with counseling, individuals who received
methadone alone showed minimal improvement in reducing opioid use (72). The
addition of counseling produced significantly more improvement. The addition
of on-site medical, psychiatric, employment, and family services further
improved outcomes. In another study with patient with DSM-IV–defined
cocaine dependence, individualized drug counseling, together with group
counseling, was quite effective in reducing cocaine use (73). Thus, it appears
that this approach has great utility in outpatient treatment for both heroin and
cocaine addiction.
Supportive expressive psychotherapy is a time-limited, focused
psychotherapy that has been adapted for individuals with heroin and cocaine use
disorders (74). The therapy has two main components: supportive techniques to
help patients feel comfortable in discussing their personal experiences and
expressive techniques to help patients identify and work through interpersonal
relationship issues. Special attention is paid to the role of drugs in relation to
problem feelings and behaviors and how problems may be solved without
recourse to drugs. The efficacy of individual supportive–expressive
psychotherapy has been tested with patients receiving methadone treatment who
had co-occurring psychiatric disorders (75). In a comparison with patients
receiving drug counseling only, both groups fared similarly with regard to opioid
use, but the supportive–expressive psychotherapy group had lower cocaine use
and required lower doses of methadone. In addition, the patients who received
supportive–expressive psychotherapy maintained many of the gains they had
made. In an earlier study, supportive–expressive psychotherapy, when added to
drug counseling, improved outcomes for opioid-dependent patients in
methadone treatment with moderately severe psychiatric problems (76). There
are a wide scope of other addiction-specific therapies discussed elsewhere in this
textbook.
Treatment of the Adolescent With

Multidimensional Family Therapy
Multidimensional family therapy is an outpatient, family-based drug treatment
approach for adolescents. It approaches adolescent drug use in terms of a
network of influences (individual, family, peer, and community) and suggests
that reducing unwanted behavior and increasing desirable behavior occur in
multiple ways in different settings. Treatment includes individual and family
sessions held in the clinic, in the home, or with family members at the family
court, school, or other community locations. During individual sessions, the
therapist and adolescent work on important developmental tasks, such as
decision-making, negotiation, and problem-solving skills. Teens acquire skills in
communicating their thoughts and feelings to deal better with life stressors and
vocational skills. Parallel sessions are held with family members. Parents
examine their particular parenting styles, learn to distinguish influence from
control, and learn how to have a positive and developmentally appropriate
influence on their child (77).
Multisystemic Therapy
Multisystemic therapy addresses the factors associated with serious antisocial
behavior in children and adolescents who use drugs. These factors include
characteristics of the adolescent (eg, favorable attitudes toward drug use), the
family (poor discipline, family conflict, or parental drug use), peers (positive
attitudes toward drug use), school (dropout, poor performance), and
neighborhood (criminal subculture) (68). By participating in intense treatment in
natural environments (homes, schools, and neighborhood settings), most youths
and families complete a full course of treatment. Multisystemic therapy
significantly reduces adolescent drug use during treatment and for at least 6
months after treatment. Reduced numbers of incarcerations and out-of-home
placements of juveniles (78) offset the cost of providing this intensive service
and maintaining the clinicians’ low caseloads (79). For more information on
treatment of adolescents, see Section 13 of this textbook.
Computer-Assisted Therapy
There is a growing body of literature that supports the use of technology in the
treatment of the addiction, using computer-assisted therapies (CAT) through
online counseling, self-help resources, and text messaging. A number of
randomized controlled trials (RCTs) have been conducted in recent years
examining the efficacy of CAT for addiction to a number of substances, with
some of these demonstrating that this intervention approach may significantly
reduce substance use behavior and biochemical measures of substance use.
Formal CAT programs are usually clinician facilitated, although some are
developed to be used independently by the addicted individual. A number of
online CAT programs were developed and evaluated in RCTs, including a
smoking cessation program, CHESS (80), and a computerized version of
cognitive–behavioral therapy (CBT4CBT). When compared with participants
receiving standard treatment, participants receiving the CBT4CBT and/or the
CHESS program provided a significantly higher number of negative urine
samples and achieve longer periods of abstinence (81). Further CAT programs
are used throughout the addiction treatment field, although there is a paucity of
RCT data to support their use. For example, the MAP Program at the Origins
Recovery Centers and Hazelden MORE (My Ongoing Recovery Experience)
program are CAT programs used within these treatment centers that are not
available to individuals who are not receiving such “in-house” treatment.
In addition to formal CAT, online counseling and information programs have
also been evaluated. In an RCT with 206 young people with cannabis use
problems, the “quit the shit” program (82) was evaluated. This program
incorporates self-help, counseling, keeping a diary of cannabis consumption, and
monitoring of a range of mental health outcomes such as anxiety and depression.
Compared to wait-list controls, participants randomized to the “quit the shit”
program were demonstrated to have significantly reduced self-reported cannabis
use, and there were some small improvements in mental health outcomes.
Removing the need for direct therapist involvement, online self-help
resources for the addiction have also been evaluated in a number of studies. For
example, an RCT of an online, multicomponent, self-help program for problem
alcohol consumption (83) with 261 problem drinkers provided some support for
the efficacy of this kind of intervention. When compared with control
participants exposed to an online brochure regarding the effects of unhealthy
alcohol consumption, participants exposed to the self-help program reduced their
self-reported alcohol consumption significantly more than the control group.
The Internet may also provide a useful format for screening for substance
problems and also for providing brief interventions. An RCT of a Web-based
alcohol screening and brief intervention program (84) with 576 problem drinking
university students found that compared to no-treatment controls, those using the
program experienced a reduction in problem drinking. This reduction in drinking
was accompanied by a reduction in associated psychosocial problems, with both
of these outcomes being maintained at 6- and 12-month follow-up.
Moving beyond online programs, the use of technology to treat addiction has
extended into the use of cell phones and text messaging interventions. For
example, the “txt2stop” tobacco treatment program has recently been evaluated
using an RCT methodology with 5524 smokers. Compared to controls,
significantly more participants using the “txt2stop” program achieved abstinence
from smoking at 6-month follow-up, with this abstinence being biochemically
verified. These findings appear to be partially verified by a Cochrane review
(85), in which five studies were included in a meta-analysis, resulting in an
outcome indicating an overall benefit at 6-month follow-up in terms of
abstinence. However, the authors of the review report that this finding should be
interpreted with caution due to some heterogeneity across the five studies
included. Some research has now started looking at the efficacy of using cell
phone technology in treating unhealthy alcohol (86) and cannabis use (78),
although more research is needed before any firm conclusions can be drawn
regarding the efficacy of such a treatment approach for the addiction.
PHARMACOLOGICAL THERAPIES
Opioid Agonist Treatment

Opioid agonist treatment usually is conducted in outpatient treatment settings,
such as federally regulated opioid treatment programs (methadone clinics, which
may also provide buprenorphine) or a physician’s office (buprenorphine). Their
services are discussed in more detail elsewhere in the textbook, including
Section 7. These programs provide methadone or buprenorphine administered
orally for a sustained period of months to years and at a dose sufficient to
prevent opioid withdrawal while also blocking the effects of nonprescribed
opioid use so as to reduce reinforcement to continue with such behavior. Also,
these medications decrease opioid craving. Buprenorphine is currently available
in formulations that are taken sublingually and buccally or implantable.
Sublingual and buccal formulations most commonly combine buprenorphine
with the drug naloxone, an opioid receptor antagonist. Naloxone has no effect
when the medications are taken as prescribed, but if an individual with opioids in
their system attempts to inject the buprenorphine/naloxone combination, the
naloxone will produce severe withdrawal symptoms. Thus, this formulation
lessens the likelihood that the drug will be used for self-reward or be diverted to
others. The use of buprenorphine for opioid use disorder requires that the
prescriber be trained in formal, certified programs resulting in a waiver from the
Drug Enforcement Administration allowing them to prescribe it. The availability
of office-based treatment for opioid addiction is a cost-effective approach that is
generally far more available in many communities compared to methadone (87).
Patients stabilized on adequate, sustained doses of methadone or
buprenorphine can function normally. They can hold jobs, avoid the crime and
violence of the drug culture, and reduce their exposure to HIV and hepatitis C by
stopping or decreasing injection drug use and drug-related high-risk sexual
behaviors (88–94). Indeed, the infection-reducing benefit of substance use
treatment programs is most robust in those programs providing opioid agonist
therapies (81–84). Patients stabilized on opioid agonist treatment can engage
more readily in counseling and other behavioral interventions that are essential
to recovery and rehabilitation. The most effective opioid agonist treatment
programs include individual or group counseling and provision of, or referral to,
other needed medical, psychological, and social services. Criteria for
management in the physician’s office have been described, and physicians are
advised to engage with local providers of substance use disorder care to provide
services that may be beyond the scope or ability of the office-based practice.
Antagonist Treatment Using Naltrexone

Antagonist therapies are used to block or counteract the physiological or
subjective reinforcing effects of substances. Treatment of patients with opioid
use disorders with naltrexone usually is conducted in outpatient settings,
although initiation of the medication often begins after medical withdrawal
management or in a residential setting. Naltrexone is a long-acting synthetic
opioid antagonist with few side effects that is taken orally, either daily or three
times per week, for a sustained period. An extended-release formulation of
naltrexone is also available and has shown some efficacy in select populations
(95). Candidates for therapy with naltrexone must be medically detoxified and
opioid-free for several days before the drug can be given, to avoid precipitating
opioid withdrawal. When naltrexone is used in this fashion, it blocks the effects
of self-administered opioids, including euphoria. The theory behind this
treatment is that the repeated lack of the desired opioid effects, as well as the
perceived futility of using the opioid, will gradually extinguish the desire to use
opioids. Naltrexone itself has no subjective effects or potential for misuse and is
not addicting. Patient noncompliance is a common problem; therefore, a
favorable treatment outcome requires that there also be a positive therapeutic
relationship, effective counseling or therapy, and careful monitoring of
medication compliance (96). Many experienced clinicians have found naltrexone
most useful for highly motivated, recently detoxified patients who desire total
abstinence because of external circumstances, including impaired professionals,
parolees (97), probationers, and prisoners in work release status. Patients
stabilized on naltrexone can function normally. They can hold jobs, avoid the
crime and violence of the street culture, and reduce their exposure to HIV by
stopping injection drug use and drug-related high-risk sexual behaviors.
Compared to naloxone, naltrexone has a good oral bioavailability and a
relatively long half-life. Its availability as a long-acting injectable preparation
may improve treatment adherence (98,99).
CONCLUSION
Although this chapter has not been exhaustive in its coverage of all the
behavioral or medication treatments in use, other pharmacotherapies and
psychotherapies are in various stages of development. Even so, dissemination
and implementation remain a challenge that require the highest priorities if
patients with substance use disorders in various clinical settings are to benefit
from the advances since the 1960s and those in the future.
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CHAPTER 29
Integrated Care for Substance Use
Disorder
Keith Humphreys, Mark McGovern and A. Thomas
McLellan
CHAPTER OUTLINE
Introduction
A Brief History of 20th Century Addiction Treatment in the United States
Toward Integrated Care for the Population of People with SUDs
Conclusion
INTRODUCTION
Healthcare professionals treat many patients with acute health problems ranging
from runny noses to broken bones. But the bulk of the work of the US healthcare
system revolves around chronic health conditions: congestive heart failure, back
pain, depression, diabetes, obesity, hypertension, and infectious diseases such as
HIV and HCV. Primary care physicians screen for such problems and treat
identified cases to the limits of their knowledge and ability. In working to
manage such conditions in collaboration with patients, primary care doctors are
backed up by specialists with whom they share information and with whom they
collaborate when cases are more severe or complex.
This efficient, guideline- and protocol-driven approach to managing chronic
health conditions is the norm across most of medicine. But in most of the
healthcare system, this model has not been optimally applied to gambling or
substance use disorders (SUDs). This chapter explains how this unfortunate
situation arose and describes an alternative approach in which modern,
empirically grounded techniques of providing integrated chronic disease
management can be implemented for persons with SUDs.
A BRIEF HISTORY OF 20TH CENTURY

ADDICTION TREATMENT IN THE
UNITED STATES
In describing how addiction treatment evolved in the healthcare system, one has
to begin by observing the long-term cultural ambivalence about siting it in health
care at all. Following from the view that people with SUDs have bad character
for which they should be punished, criminal justice has often been the lead
public entity tasked with responding to people with SUDs. For example, the first
federal drug treatment programs in the United States (at Lexington, Kentucky
and Fort Worth, Texas) were closer to prisons than hospitals. Many “tough love”
and “scared straight” interventions have emerged over the years for offenders
with SUDs, on the premise that sufficiently punitive measures will “teach them a
lesson” and cause them to reform.
SUD treatment has also sometimes been considered part of social welfare,
for example, outreach and counseling done in homeless shelters and Salvation
Army soup kitchens. This framework is gentler than punitive interventions and
has often been applied by dedicated people in some of the most resource-poor
parts of the country. Without demeaning in any way the commitment of such
programs to helping the impoverished and downtrodden, it is descriptively
correct to say they are not part of the healthcare system. They generally employ
no medically trained individuals, provide no medical interventions, and do not
generally think of themselves as treating a discrete medical disorder so much as
saving damaged souls.
Even psychiatric medicine did not make SUD a genuine part of the
healthcare system for much of the 20th century. From the time of Freud,
psychiatrists generally conceptualized SUD as a symptom, perhaps a
maladaptive attempt at “self-medication” of an underlying condition. The
(empirically unsupported) premise was that when the “real problem” is resolved,
SUD will be cured in tow.
SUD treatment did not gain a significant foothold as a specialized form of
health care until around 1970 (1,2). The main drivers of the change were the
emergence of a drug culture among college-aged baby boomers, the return of
opioid-addicted veterans from Vietnam, a flood of federal government money
for SUD treatment and research (the National Institutes focusing on alcohol and
other drugs were founded in the early 1970s), and the development and
dissemination of an effective, easily scaled medical intervention for opioid use
disorder (methadone maintenance).
With the exception of the Veterans Health Administration, the mainstream
healthcare systems of the 1970s were neither equipped for nor particularly eager
to accept SUD patients. Thus, at the time, the new system was designed and
financed separately. Originally, state systems were well funded and
organizationally placed at the highest levels of government bureaucracy,
reflecting the political importance of the issue. Many of the initial “State
Systems Administrators” (SSAs) were physicians and often personal friends of
the governors within those states—virtually all SSAs were in state cabinet–level
positions (3). The treatments that emerged were largely based upon the
prevailing schools of thought from a very wide range of care providers (eg,
psychiatrists and other physicians, psychologists, nurses, correctional
counselors) and perhaps even more based upon the individual experiences with
personal recovery from SUDs (2).
SUD treatment advocates had their own reasons to want a segregated
system. Because there were concerns among federal and state policy makers that
funds for SUD treatment would be quickly appropriated by politically stronger
mental health and mainstream medical practitioners, special efforts were made to
create targeted funding streams. In parallel, legitimate concerns that sharing
health information about SUDs could lead to harm to patients (eg, police staking
out methadone clinics and arresting patients suspected of dealing or possessing
narcotics), health information that would normally be in a patient’s record was
walled off such that SUD treatment professionals only communicated among
themselves (ie, under Section 42 of the Code of Federal Regulations). Unique
regulations for SUD treatment went beyond health information to cover many
other matters regarding the delivery, staffing, and outcomes of health care.
All the normal channels that connected other specialties to the healthcare
system—funding streams, shared information, professional collaboration, and
common regulations—were thus cut off for SUD treatment. As a result, it
functioned largely in its own world, a nomadic specialty outside of a healthcare
system, the rest of which would become increasingly integrated in the coming
decades.
Being isolated had downsides. The much-heralded treatments of the period
failed to “cure” SUDs in the fashion expected of treatments for acute illnesses,
and the field did not have the alliances needed to continue to make the case for
resources. Healthcare spending became an increasingly important issue within
the private sector. Employers became disenchanted with Employee Assistance
Program efforts to control workplace substance use and began to reduce
employee healthcare benefits for SUD treatment through managed care
organizations (4). Meanwhile, in the public sector, the political positions of most
state alcohol and drug prevention and treatment authorities became reduced in
visibility, budget, and organizational power (5). By the first decade of the new
century, there were only two states whose SSAs remained in the cabinet (3,6).
Addiction treatment programs and professionals became stigmatized and
marginalized in much the same way as were the patients for whom they cared.
In the rest of the healthcare system, the expansion of pharmacotherapy
benefits in private insurance packages fostered the development of new
medications with the potential for significant cost savings from reduced hospital
stays and fewer retreatments. However, in the SUD field, care was already very
inexpensive; there were few SUD medicine specialists and enduring ideological
conflicts among those specialists regarding the appropriateness of medications
for SUDs. These belief-based disputes fractionated an already small market.
Thus, there was little political pressure within the field for insurers (public or
private) to include medication benefits—thus, no incentive for pharmaceutical
firms to invest in SUD pharmacotherapies. Consequently, until the late 1990s,
there were very few existing medications available to treat SUDs and little active
research to develop new ones (7,8).
Another critical consequence of SUD treatment’s historical isolation is that it
tended to care only for high-severity cases. For decades after the specialty
system emerged to care for severe cases within its own silo, no empirically
grounded technologies were developed for primary care practitioners to screen
for and intervene with risky, mild or moderately severe SUDs (nor was there any
expectation that this was an important role of primary care providers).
Furthermore, there were no clear clinical pathways or protocols as to how severe
patients identified in primary care could be connected to specialty treatment.
Individuals with SUDs thus tended to receive little help until they were in an
acute or life-threatening situation, for example, if they required an inpatient
withdrawal management or were arrested on a substance-related charge.
As with most other disorders, providing care only when patients are at their
worst and their condition at the most advanced stage results in poor outcomes.
This fosters healthcare providers’ perceptions that SUD treatment is ineffective
and that there is little hope for people with SUDs.
The lack of a connection of SUD treatment to the rest of the healthcare
system also had negative implications even when initial outcomes were positive.
SUD treatment programs usually had nowhere to send successfully treated
patients in early recovery for ongoing management within the healthcare system.
(Many people went to and benefitted from peer recovery support groups, but
those are outside the formal health system.) If a primary care physician were
caring for a patient who had just spent 28 days in an alcohol rehabilitation unit
or 6 months in a therapeutic community or was even concurrently receiving
methadone from an opioid agonist treatment program, the physician would
usually not even know it unless the patient volunteered the information.
Practically, this meant that the usual follow-up procedures that would help after
other specialty care did not happen for SUD, which likely reduced the number of
individuals who translated their specialty treatment gains into sustained
recovery. It probably also sometimes unwittingly resulted in iatrogenic harms
such as primary care providers prescribing medications that undermined the
potential benefit of SUD pharmacotherapies or were addictive themselves (eg,
benzodiazepines for sleep or anxiety, narcotics for pain).
TOWARD INTEGRATED CARE FOR THE

POPULATION OF PEOPLE WITH SUDS
In recent decades, opportunities to better integrate SUD treatment with the rest
of the healthcare system have become available, for five main reasons. First,
there have been improvements in insurance coverage under a number of laws,
including the Medicare Improvement for Patients and Providers Act of 2008, the
Wellstone-Domenici Mental Health Parity and Addiction Equity Act of 2008,
and the 2010 Affordable Care Act. Second, there have been new developments
in addiction-related technologies such as better screening instruments, briefer
interventions for early-stage or less severe problems, medical management
strategies usable in primary care, and evidence-based pharmaco- and
psychotherapies that can be deployed in a range of settings. Third, as the “War
on Drugs” has waned, more patients and primary care doctors are increasingly
comfortable discussing substance use as they would any other health concern.
Fourth, changes in privacy regulations and information technology are making
team-based care of SUD less difficult. Fifth, because of the rapidly expanding
complexity of general medicine and specialty care, large group practices,
multidisciplinary collaboration, and team-based care have all but completely
replaced the solo practitioner.
In this new environment, people with SUDs can interact with the healthcare
system just as do people with other conditions that vary in severity and
chronicity. A well-known model for conceptualizing and organizing such care is
the chronic care management model (CCM). The CCM model is a long-term,
proactive strategy involving multidisciplinary teams instead of just a single
physician. Methods include patient registries, standardized protocols and
metrics, measurement-based care, and an expectation of a long-term relationship.
The ultimate goal of the CCM model is engaging patients and their families and
providing them with the necessary information, options, strategies, and supports
necessary for continued self-management of their chronic disease. Rather than
providing reactive, acute care episodes of expensive hospital care following a
serious worsening of the condition, the CCM is decidedly proactive, using a
range of mechanisms to stay in contact with patients and to provide anticipatory
clinical care options to maximize disease control and to prevent relapses that can
lead to emergency department visits, hospitalizations, and poor health outcomes
(9).
There is mounting evidence indicating that the CCM model is more effective
than is standard clinical care (9), and CCM is thus understandably being
increasingly applied to SUD care. Some evaluations have been negative (eg, the
AHEAD trial, 10). Notably, it is effective in the treatment of behavioral health
conditions such as depression (10), as well as physical illnesses (9,11); is more
appreciated by patients and physicians (12); and does not appear to cost more
than traditional clinic care (13).
It is thus reasonable to ask what an appropriately conceptualized and
organized continuum of care for SUDs might look like and how patients might
be managed using a CCM model. In this regard, four linked clinical stages are
suggested (see Table 29-1), each with a specific clinical purpose that is related to
the overall goal: patient empowerment through self-management to maximize
functioning and reduce relapse risk. The stages are Early Identification/
Intervention, Stabilization, Clinical Monitoring/Management, and Patient Self-
Management.
TABLE 29-1 Four Stages of CCM for Substance Use

Disorders
Five introductory points are important prior to discussion of the stages of care.
First, primary care practitioners will notice that these stages of care, and many of
the clinical activities that occur within each, are quite similar to those associated
with the management of other chronic illnesses. Of course, there are special
clinical issues associated with SUDs—as there are special issues associated with
chronic noncancer pain, sleep disorders, diabetes, and asthma. But the overall
goals for the CCM model are similar across virtually all chronic illnesses.
Second, the CCM model and the suggested stages are not just for the
management of “addiction” but rather for that of the full spectrum of unhealthy
substance use and SUDs. This can be a difficult issue for both general and
specialist practitioners. Many general practitioners have learned only about SUD
of the higher-severity levels and fail to recognize the more highly prevalent,
lower-severity SUDs in their practices. Experienced SUD professionals
sometimes dichotomize any inappropriate substance use as definitive evidence
for “addiction.” This too can limit the possible benefits of care. Through a
shared decision-making process, a customized, patient-centered variety of
clinical goals can be attractive to and appropriate for individuals with lower-
severity hazardous substance use (eg, lower-risk use) even though they are
generally not appropriate for those who meet criteria for serious SUDs.
Third, because these stages and their clinical goals are conceptually linked,
many treatment practices will have a role in more than one stage—but to address
different problems. For example, one medication may be prescribed within the
stabilization stage to reduce withdrawal symptoms, whereas a different
medication may be appropriate in the clinical management stage to ameliorate
the intensity of craving episodes. An important implication is that outcome
expectations and evaluation methods are most useful when tied directly to a
specific stage of care. For example, under the CCM model, it is not informative
to ask “Is naltrexone effective in the treatment of alcohol use disorder?” A much
more clinically informative question would be “Is naltrexone effective in
reducing alcohol craving among well-stabilized patients receiving clinical
monitoring and management?”
Fourth, there are as yet very few clear biological or behavioral markers to
guide clinical decision-making in questions of transition among these stages. For
example, an HgA1c reading below 6% and a blood pressure of 140/80 are good
markers of control in other medical disorders. Biological measures for substance
use (eg, breath, blood, urine, and/or hair samples) and physical consequences
(eg, liver function tests) are available, but they have not been integrated with
care monitoring protocols as well. This is in part because SUDs have only
recently been studied as chronic illnesses. But, as is true with many other
chronic illnesses, many comorbid conditions, genetic factors, and social
determinants of clinical progress add complexity to clinical management.
The final point—a new one for experienced “addiction” treatment providers
—is that the clinical stages are not isomorphic with specific settings or
modalities of care. Changes in insurance coverage, advances in medication and
intervention development, and new forms of electronic communication and
information exchange offer new opportunities to achieve the goals of every stage
of care in different settings (eg, primary care office) or with previously
unavailable modalities of care (eg, nursing home visits, new medications, a next
generation of peer recovery support groups, including via connections through
social media).
The Early Identification/Intervention Stage of

Care
Clinical Goals in the Early Identification/Intervention
Stage
The main goal of this stage of the care continuum is to inform and motivate
change among individuals (adolescents or adults) whose substance use is
frequent and/or intense enough to risk their health and well-being. This may be
particularly important for those with other diagnosed medical or psychiatric
conditions. Once identified, a linked goal of this stage of treatment is to use the
power of the medical teaching moment as well as clinical techniques such as
motivational interviewing to help patients accept that their substance use may be
a problem and that they are capable of reducing their use. This approach is often
based on patient education, connecting the dots between a patient’s substance
use and other life problems, which were previously perceived as unrelated.
Initial screening and brief motivational interventions should conclude with an
agreed-upon target for use frequency and amount and an identified plan by
which the patient will reduce their use. It is critical that the patient is monitored
for substance use frequency, risk, and consequences, at least weekly for the first
month following the initial intervention and biweekly to monthly over the
ensuing 3-4 months. The monitoring can occur through telephone or electronic
contact methods to check the effectiveness of the patient’s efforts and to offer
support and encouragement for those efforts.
Clinical Practices Associated with the Identification and
Early Intervention Stage
Screening and brief interventions are targeted at patients with unhealthy
substance use (particularly at-risk alcohol use), and no study shows they are
effective with people who have high-severity SUDs. Thus, postscreening
monitoring of patient alcohol and other substance use will be an essential part of
clinical decision-making in these cases. If monitoring reveals that a patient
cannot even with great effort reduce substance use to levels that no longer pose
risk to health and well-being, this will be an indication of a more serious
problem. In fact, this loss of personal control, and continued use despite
consequences, is suggestive of a SUD. Much as antibiotic-resistant infections are
diagnosed in part by the failure of first-line antibiotics, failure of brief
intervention is an indicator that a SUD is likely more than mild in severity. In
these cases, an important secondary goal from this stage of care is to have those
patients be open to recognize and self-observe that they may have a more serious
SUD and come to appreciate that more intensive treatment is necessary.
Therefore, in practice, achieving this level of patient acceptance generally
involves collaboration, repeated motivational interviewing sessions, engaging
supportive significant others, and offering practical suggestions for coping with
urges and cravings as well as high-risk situations—always accompanied by
reviewing the patient’s personally accumulating evidence. Clinical practices that
have been effective in this stage of care are screening for substance use and brief
motivational interventions to increase awareness and promote reductions in use.
At this stage, it is crucial for the healthcare provider to empathize with the
patient including any shame and guilt about the struggle to control their
substance use. Historical remnants of the “addiction as character flaw” remain
pervasive. In addition, at a cognitive neurobiological level, brain impingement
accrues and causes deficits in insight, judgment, memory, and, most
significantly, the self-control regarding the substance to which the person is
addicted.
Screening
Beyond the fact that identifying and addressing early-stage SUDs is an important
public health problem in itself, primary care practitioners can often improve the
outcomes and reduce the costs of treating other illnesses simply by identifying
and managing co-occurring substance use problems (14). For example, the
PRISM project commissioned 33 systematic reviews describing the role of
alcohol and other substance use problems in the course, complications,
outcomes, and costs of treating prevalent chronic illnesses (15). These reviews,
published in mainstream medical journals, showed that “medically harmful”
drinking or other substance use can significantly impair the diagnosis,
complicate the treatment, and elevate the costs of most chronic illnesses.
Harmful alcohol and other substance use problems can now be reliably and
accurately identified through standard screening instruments available in
computerized, paper and pencil, or individual interview formats.
Brief Motivational Intervention(s)

There has now been broad development and testing of several brief therapies
typically consisting of two to six sessions. One-session interventions such as
motivational interviewing are considered advice and are typically administered
within medical contexts (14). Brief therapies such as motivational enhancement
therapy (16) are designed to promote problem recognition among reluctant or
unaware patients with SUDs, to foster a sense of willingness and ability to
address the problem, and, often, to promote engagement in treatment.
Brief interventions have been tested extensively in over one hundred trials
with alcohol- and other drug-dependent individuals, usually as a strategy for
encouraging non–treatment-seeking individuals to enter into formal treatment
but also as a treatment intervention (17). Because of their brevity and low
reliance on treatment compliance, they have been particularly attractive to
physicians caring for patients with alcohol use disorder in emergency medical
settings, but they have also been used successfully in primary care settings (18).
Brief intervention (ie, educational and motivational interventions lasting <10
minutes) and brief treatment (similar interventions of two to five sessions)
studies within these populations have often shown significant reductions in
substance use (17). At the same time, brief interventions should be expected to
fail a significant portion of the time, in which case they are diagnostic of a more
serious disorder.
Indications for Transition to a Different Stage of Care

In cases in which monitoring reveals significant reductions in the quantity and
frequency of substance use below the levels that may be medically or socially
harmful, this will signal a transition to the patient management stage of care. In
that stage, formal clinical interventions are typically not needed. The patient is
educated and motivated to keep substance use at low levels, has a number of
techniques to achieve these reductions, and, ideally, is well supported by family
and social relationships to control their use.
It is not presently known how long or with what frequency clinical
monitoring should be undertaken before making the suggested transition—this is
an important subject for future clinical research. Similarly, there are very few
well-researched monitoring methods or social support alternatives to help those
with “unhealthy use” to reduce that use—again, an important research topic with
great clinical and practical significance.
As mentioned, failure of lower-level intervention indicates that there may be
a more serious SUD. Among the first follow-up activities suggested in such
circumstances is a full, standardized assessment of the patient’s substance use
history and their use-related medical, personal, and social problems and
resources. That assessment should provide clinical suggestions for a more
intensive intervention. If there has been protracted and/or severe recent use, the
suggested next stage of care may require a period of stabilization of physical
and/or emotional symptoms associated with use of substances or gambling that
has become medically unhealthy or is otherwise eroding psychosocial
functioning. Following completion of that stabilization stage, transfer becomes
possible to the clinical monitoring/management stage of care within either a
primary care setting or an outpatient specialty SUD treatment program.
There are as yet no clear guidelines from research regarding which of these
options is better or for which types of patients and problems. In both cases, the
goal is to help the patient regain control of their substance use—which may
require some patients to abstain totally—and it will be important to negotiate
frankly with the patient about available options and navigate person-centered but
realistic goals from those options.
The Stabilization Stage of Care

Clinical Goals in the Stabilization Stage
Alcohol and other substances with addictive potential often cause significant
physical and emotional problems directly due to the development of tolerance
and/or indirectly due to long periods of sleep disturbances, poor nutrition, and
general lack of personal care. The purpose of the stabilization stage of treatment
is not to produce cure or lasting sobriety, but rather to prepare an unstable patient
to do well in a subsequent clinical monitoring/management stage of care.
Significant physiological withdrawal is not present in all cases—even in those
with more serious forms of addiction. However, prolonged, heavy alcohol,
opioid, or sedative/tranquilizer use may produce a characteristic physiological
withdrawal syndrome of several hours to several days or even weeks following
the last use of the substance (depending upon the type, dose, and
duration/frequency of use). Users of amphetamine, cocaine, and cannabis can
also experience substantial emotional and physiological symptoms requiring a
period of stabilizing care.
Sustaining motivation and ultimately engaging the stabilized patient into
some form of continuing care involving monitoring and management (in a
residential or outpatient specialty care setting or in a primary care setting) are an
important clinical goal of this stage of treatment because stabilization alone is
rarely effective in helping patients achieve lasting recovery—particularly
patients with more severe and/or chronic addiction. Thus, this stage of treatment
is the best considered preparation for continued rehabilitation.
Clinical Practices Associated with the Stabilization Stage

The major components of this stage of care include medications to relieve
physical and emotional distress symptoms and to reduce craving. These
medications are typically accompanied by rest, patient education, and
motivational forms of therapy—usually in the context of a residential or hospital
setting. There have been significant advances in the use of medications to reduce
the medical dangers of withdrawal and also to alleviate the associated
discomfort. This area of addiction medicine is quite specialized and has been
reviewed elsewhere (7,8), including in Section 6 of this textbook.
Because stabilization is typically short (3-7 days) and because patients’
attention and concentration may be compromised for much of this period,
extended behavioral/psychosocial therapies within this context are not typically
possible. However, the same brief interventions and brief therapies described in
the early identification/intervention stage of care are also practical in this
context. In this stage, the goal of psychosocial therapy should generally be to
help the patient understand and accept that they have a SUD and that they have
the ability to manage the problem through continued participation in some form
of continuing care involving monitoring and management.
What are the indications for transition to a different stage of care? There are
typically clear and standard biological and behavioral indicators of both
physiological and emotional stabilization (vital signs, sleep pattern, appetite,
mood). There is great variability in the time required to achieve physical and
emotional stabilization depending upon the nature, duration, and intensity of the
substance(s) used and the general physical and emotional health of the affected
patient. However, most patients make rather rapid and often dramatic
improvements in the standard indicators within 3-7 days of medical care.
There is only one recommended transition from the stabilization stage, and
that is to some form of clinical monitoring/management. Any patient who
requires physiological and emotional stabilization is unlikely to do well with a
less intensive stage of care. The clinical monitoring/management stage of care
may occur within the primary care setting or within a specialty addiction
treatment program.
Although the ASAM Criteria offer rationale as to placement of patients by
level of care, there are few empirically derived guidelines on which of these
options is better or for which types of patients and problems. Regardless of
setting, the goal is to help the patient develop the capability, probably with
professional help, to manage their substance use. Again, it is possible for less
chronically or severely affected patients to achieve “control” through careful
moderation of their use (19). For patients with more protracted and/or severe use
problems, abstinence may be the only way to reduce risk and lead a functional
life. It will be important to negotiate frankly with the patient and their family
about their options for attaining and maintaining some relief and stability. The
response to treatment will shape subsequent and ongoing treatment decision-
making. Regardless of the care setting, patients entering (or reentering) the
clinical monitoring/management stage of care will likely require a rather
intensive combination of individual, group, or family therapies; contingency
contracting; and/or one or more medications. Important at this stage will also be
the stabilization of physical and psychiatric comorbidities, which could
complicate and undermine the addiction therapies.
The Clinical Monitoring/Management Stage

of Care
Clinical Goals in the Monitoring/Management Stage
Clinical monitoring and management are the most variable—in time, procedure,
and patient eligibility—of all the stages of care. It is appropriate for patients who
are physically and emotionally stabilized and who have at least gained some
capacity for self-regulation of their urges to use substances—through clinical
care provided in the early identification/intervention or stabilization stages.
Clinical goals for this stage of care are to maintain the reductions in (or
elimination of) substance use, by providing care for the medical and psychiatric
as well as social and environmental problems that were identified in the
assessment as contributors to the substance use problems, and to continue
monitoring for relapse threats. In practice, this stage of care may last 3-9 months
and can involve varying numbers and frequencies of medications, psychosocial
therapies, and adjunctive social services (depending again upon the severity and
complexity of the patient’s problems). One important resource within this stage
of care is the availability of a living environment that is free from active use, as
this is a risk factor for relapse. This type of living arrangement may be available
within the family home, in drug-free housing, or in a residential specialty SUD
treatment setting.
An additional and important goal from this stage of care is to educate and
engage the patient’s family and social relationships to assist in the monitoring
and support of the patient’s efforts to control their substance use. Several long-
term studies of recovery from SUDs have identified ongoing support from
family and social networks as key factors in recovery, as well as the
development of prosocial, healthy activities and behaviors that are inconsistent
with substance use (20–23). In summary, the continued maintenance of
abstinence or very reduced substance use, good health—including mental health
—and good social function in the clinical management/monitoring stage of care
has the following four goals:
1. Maintain physical and emotional stability initiated during stabilization.

2. Enhance and sustain reductions in alcohol and drug use (more severe and
chronic patients will require complete abstinence).
3. Teach, model, and support behaviors that lead to improved personal physical
and mental health, family, and social function and reduced threats to public
health and public safety.
4. Motivate behavioral and lifestyle changes that are incompatible with
substance use.
Clinical Practices Associated with the Clinical

Management/Monitoring Stage
FDA has approved medications for treating SUDs. Most of these medications
have been tested on more chronic and severely affected patients—it is not
presently known whether or to what extent medications are effective in early-
stage unhealthy use of alcohol and other drugs. In addition, these medications
have been studied over relatively short periods of time (12 weeks on average,
some up to 1 year). Questions remain about the course and duration for addiction
medications. This is an opportunity for medical researchers. For this reason, we
will not review these medications extensively here, but they are the subject of
much greater review elsewhere (7,8) and in this textbook.
Addicted individuals with concurrent psychiatric problems are more likely to
drop out of standard SUD treatments, less likely to benefit from those
treatments, and more likely to relapse early following those treatments. There is
increasing evidence that the prescription of appropriate psychotropic
medications can alter that prognosis (24,25). Integrated psychosocial therapies,
which address both the mental health and substance use issues within the same
approach, may also be effective.
Clinical management and monitoring will often involve the provision of
behavioral/psychological therapies. Significant clinical research over the past
two decades has led to the development, testing, and wide availability of
psychosocial therapies to help patients control their urges to use substances but
also improve skills to manage emotional and relationship problems that so often
accompany SUDs. Effective models (described elsewhere in this volume)
include contingency management approaches, cognitive–behavioral therapy, 12-
step facilitation counseling, and behavioral marital therapy. Most of these
therapies have been studied in outpatient specialty care settings—and it remains
for additional research to investigate their role in other settings within the
clinical management/monitoring stage of care.
It is extremely common for the SUD-focused psychological therapy and
pharmacotherapy providers to be different individuals (eg, a physician and a
clinical social worker). This creates advantages in terms of cost and efficiency,
but also requires more coordination, which can be challenging depending on
how the care system handles information sharing regulations, whether the two
providers have a compatible approach to care, and whether a positive and
respectful interdisciplinary atmosphere prevails on the care team. As problems
on any of these fronts can result in worse care for the patients, the care team
must prioritize the smooth working of their own relationship. Mutual respect for
one another’s professional voice and expertise, good communication skills, and a
sense of a common purpose are key ingredients to team-based care. Lack of
parallel treatment collaboration can place the provider at increased risk for
malpractice claims. System managers should also monitor the formal procedures
and informal norms governing such care arrangements, as they are likely to
influence not only patient outcomes, but those for staff (eg, morale, burnout,
productivity).
Indications for Transition to a Different Stage of Care

Patients with more severe, complex, and chronic SUDs will likely require a
greater number and frequency of clinical practices to achieve and sustain these
clinical goals and will likely require a longer period of successful maintenance
of these goals prior to transfer to a less intensive stage of care. However, even
these intuitive assumptions have received very little research attention. There are
important opportunities to study the specific behavioral indicators of high
likelihood for successful transition to the patient management stage of care and
the particular sets of clinical interventions that are most likely to produce patient
changes that reach the designated performance threshold for transition.
Though important in all earlier stages of care, monitoring of substance use
through biological tests and patient self-report is critical in the clinical
monitoring/management stage for important clinical determinations such as
whether to increase or decrease the intensity or change the composition of
clinical practices provided to a patient and particularly whether to transition a
patient to a more intensive or less intensive stage of care. Again, there has been
little research regarding the appropriate behavioral and biological criteria for
these transitions. There are thus important opportunities for practical research in
this area.
In general, self-disclosed or positive biological tests for substances with
addictive potential or liability are an indication that there is a need for more
frequent monitoring (in person and/or through electronic media) and likely more
intensive clinical interventions. As indicated above, there are already many types
of medications, psychosocial therapies, and clinical services that may be
recommended toward the goal of reducing substance use and related problems.
The question of how long to continue any level of clinical
management/monitoring in the face of continued positive biological test results
will always be an individual clinical determination. However, in general, it is
wise to negotiate in advance of care initiation regarding the specific behavioral
goals and to get patient acceptance for more intensive clinical options if there is
not progress toward the agreed-upon goals (perhaps referral to specialty SUD
care if the patient is being managed in a primary care office or to a residential
treatment program if the patient is being managed in an outpatient treatment
program).
A more welcome but no more informed question is when to refer a well-
functioning patient with few to no indications of substance use to the personal
management stage of care. It is currently not known how long a period of
sustained abstinence should be achieved before a stable, well-motivated patient
can be expected to continue good function with little or no clinical management.
Even when clinically managed and monitored patients are able to achieve stable
periods of abstinence, the transition to personal management can be difficult and
unsettling. Among the most reliable and robust findings from clinical studies of
alcohol- and drug-addicted patients is that continued, active participation in
Alcoholics Anonymous (AA) or other social support form of recovery
maintenance is an excellent predictor of sustained sobriety and good social
function (26,27). Although this is clear in the case of severely addicted patients
treated in specialty care programs, it is not known whether or to what extent it
will hold true among less severely or chronically affected patients treated in
primary care settings. Regardless, there is much to commend referral to AA or
other peer recovery support groups. Somewhere around half of people who
attend an AA meeting never attend more than a handful of meetings, but for
those who do affiliate with such organizations, the peer support offered and life
skills taught are valuable for initiating and maintaining positive lifestyle changes
and functioning (28). Rigorous research has shown that AA participation in
combination with treatment or alone predicts better substance use and
psychosocial outcomes, and findings for other 12-step mutual help organizations
like Narcotics Anonymous and Cocaine Anonymous are also encouraging
(29,30).
The Patient Self-Management Stage

The term “patient self-management” indicates the transition from some/any form
of clinically directed care and monitoring, toward self-management by the
patient of substance use and related problems, likely with the informed
assistance of family, friends, and other community resources (eg, mutual help
groups and recovery support services).
Historically, these kinds of informal care interventions were not included as
part of formal treatment or as part of most treatment research studies—either in
the field of SUD or in other types of chronic illness care. However, with the
change in approach toward SUDs as a chronic illness, substantial research
showing the value of participation in AA and the emerging research on the value
of simply contacting, supporting, and monitoring the condition of previously
treated patients, this stage of the continuum has shown its importance. For these
reasons, there has been increasing interest in actively fostering patient
involvement in AA and other peer recovery support groups as a way of
promoting continued maintenance of health and function gains made during
formal treatment and as a hedge against reinitiation of substance use and
reutilization of expensive care options.
Goals of the Personal Self-Management Stage

The personal management stage of care shares many of the goals of the clinical
management stage of care—the essential difference is that in the latter stage,
responsibility and capability for management rest on the patient and his or her
family and social circle. In turn, it follows that one of the goals of the later
phases of the clinical management/monitoring stage is to inform, train, engage,
and practice the family and other social supports to take on these responsibilities
in a practical and effective manner. Personal management has the following four
goals:
1. Maintain physiological and emotional improvements initiated during earlier

stages.
2. Self-monitor threats to relapse and make corrections where appropriate.
3. Learn and practice more effective coping behaviors and self-care.
4. Maintain healthy relationships and social behaviors incompatible with
substance use.
Clinical Practices Associated with the Personal Self-

Management Stage
All FDA-approved medications mentioned in the prior section may also be
useful in self-management of SUDs. Craving may occur in unexpected situations
or through routine interactions with “slippery people, places, and things” (to use
an AA phrase) that were previously associated with the use of substances.
In addition, co-occurring mood disorders are prevalent and may reoccur,
particularly at times of significant life stress. Psychotropic medications can be
important in such instances, which, if handled well, will reduce likelihood of
substance use reinstatement. The assistance of these medications may provide
pharmacological support for the benefits of psychosocial interventions and peer
recovery support groups such as 12-step recovery fellowships.
Psychosocial therapies designed to engage family supports and to forge new,
healthy peer relationships may be particularly valuable as recovering patients
attempt to integrate a new recovering lifestyle into their historical environment
and relationships. However, as is true of so much of the clinical practice in this
developing field, there has been little systematic research to guide patients or
their clinicians in suggesting or selecting continuing care interventions or
practices (other than mutual help group attendance) that a patient and his/her
family can manage independently.
Peer recovery support group participation is important for many individuals.
AA remains the most prevalent form of continuing care for individuals who are
dealing with alcohol and/or other substance use problems, and these meetings
can be very helpful to a wide range of individuals including those considering
reducing their substance use, those actively participating in earlier stages of the
care continuum, those on psychotropic and/or addiction medicines, and
particularly those in the personal self-management stage. AA groups can be
found in every town and city and there is great variability among these groups.
Some groups are for particular types of individuals (gay or lesbian, nonsmokers,
atheists, individuals with co-occurring substance use and mental health
problems, etc.). Within any single AA group, it is common that some meetings
will be “open” to all individuals regardless of whether they have a SUD; some
will feature speakers who will share their stories and topic meetings where the
group discusses views on a particular aspect of recovery from substance use. The
point is that patients should attend several groups in several locations before
deciding whether to become an active participant and which group to use as the
home group.
For various reasons, AA research has begun to increase (29). This research
has shown that patients who participate in AA have much better continuing
abstinence and social performance than patients who have received rehabilitation
treatments but have not continued in AA. For example, Moos and Moos (22)
found that faster affiliation with AA and longer participation predicted better 1-,
8-, and 16-year alcohol-related outcomes. Individuals who attended AA at least
five times per week for the first year had almost a 90% likelihood of abstinence
at 1 year, and participation in AA has a causal, positive effect on alcohol-related
outcomes over and above the effects of formal treatment (22). A Cochrane
review is pending as of this publication date.
CONCLUSION
It is hoped that this version of the CCM model adapted to accommodate
management of SUDs may offer a basis to stimulate much-needed research and
new clinical management efforts. However, it is clearly a framework to be
modified rather than a sacred relic.
A more pragmatic and implementable approach with the CCM model may be
one that considers the most common behavioral health problems, SUDs, and/or
mental health conditions that are commonly encountered by general medical
practices. Epidemiological studies confirm these disorders are rarely present in
isolation, yet clinical research is largely based on singular disorders and specific
treatments (31). Unfortunately, this does not match the clinical reality of at least
comorbidity, if not multimorbidity, among the more typical complex patients in
routine practice settings. A unified CCM model that builds upon and braids the
evidence-based approaches for a variety of common conditions is needed to
guide providers and patients across the stages outlined here. Especially if we
consider general medical settings such as primary care, a unified model would
likely be more implementable by considering aspects of workflow and
workforce, unlike the more single disorder, specific targeted approaches that
presently exist. Such a unified model would build across well-defined disorder-
specific approaches (e.g., (32,33)) but more realistically address the typical
patient, the typical provider, and the typical setting within which health care
takes place (32–34).
There are significant gaps in our knowledge about the most appropriate and
effective options. Nonetheless, the conclusions possible from our developing
knowledge base are quite optimistic. There is an increasing range of evidence-
based treatment components. There are adequate medications and a medical
basis for treatment, as well as the promise of new compensation to attract and
provide a meaningful role for physicians in the treatment of SUDs. There are
also individual and family-oriented behavioral therapies that sophisticated
therapists from various backgrounds can use to reduce substance use and its
associated personal and family pathologies. Moreover, work in these important
areas is continuing with progress made each year. The possibilities for improved
integrated care for SUD have never been better.
ACKNOWLEDGMENTS
Development of this chapter was supported by the Veterans Affairs Health
Services Research and Development Service and the National Institute on Drug
Abuse.
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CHAPTER 30
The ASAM Criteria and Matching
Patients to Treatment
David Mee-Lee and Gerald D. Shulman
CHAPTER OUTLINE
Introduction
Selecting Appropriate Services
Understanding the ASAM Criteria
Assessment Dimensions
Levels of Care
Placement Dilemmas
Research on the ASAM Criteria
The ASAM Criteria Software
Conclusions
INTRODUCTION
The ASAM Criteria for the treatment of addiction-related and co-occurring
conditions have its roots in the mid-1980s. The developers of two sets of
placement criteria that were gaining some national attention at the time joined
with the American Society of Addiction Medicine (ASAM) to lead and advocate
for one national set of criteria that would unify the addiction treatment field. The
National Association of Addiction Treatment Providers (NAATP) joined with
ASAM to create the criteria by integrating and revising the Cleveland Criteria of
the Northern Ohio Chemical Dependency Treatment Directors Association
(NOCDTDA) (1) with the NAATP Criteria (2). Both NOCDTDA and NAATP
agreed to allow a third set of national criteria to supersede their organizations’
documents, despite considerable investments of time, effort, and financial
resources in developing the separate criteria.
ASAM was entrusted to lead this advocacy and in 1991 published the
Patient Placement Criteria for the Treatment of Psychoactive Substance Use
Disorders (3). Multidisciplinary groups of addiction treatment specialists,
involving counselors, psychologists, social workers, and physicians, worked to
develop one national set of consensus criteria to promote a common language
and placement guidelines for assigning patients to different levels and types of
treatment services for addiction. The ASAM Criteria were designed to help
clinicians, payers, and regulators use and fund levels of care in a rational and
individualized treatment manner. Thus, they may have helped to move the
addiction treatment field away from fixed programs to an assessment-based,
clinically driven, outcome-oriented continuum of care. The continuing
development and refinement of the criteria represent a shift from:
1. One-dimensional to multidimensional assessment—from treatment based

solely on diagnosis to treatment that addresses multiple needs
2. Program-driven to clinically and outcome-driven treatment—from
placement in a program often with fixed lengths of stay to person-centered,
individualized treatment responsive to specific needs and progress and
outcome in treatment
3. Fixed length of service to a variable length of service, based on patient
needs and outcomes
4. A limited number of discrete levels of care to a broad and flexible
continuum of care
The ASAM Criteria describe six assessment dimensions that are used to
differentiate patient needs for services across levels of care.
A second edition was developed in 1996, ASAM PPC-2 (4), and in 2001, a
revision of PPC-2 was published, ASAM PPC-2R (5). A further revision, The
ASAM Criteria (6), published in 2013, contains information to expand
application of the criteria to special populations of older adults, parents receiving
treatment concurrently with their children, people in safety-sensitive
occupations, and criminal justice populations. There are also sections on tobacco
use disorder and gambling disorder to promote a necessary continuum of
services that are still not funded and reimbursed like other substance-related and
addictive disorders. An updated Opioid Treatment Services section includes
opioid treatment programs (methadone), office-based opioid treatment
(buprenorphine), and antagonist medication (naltrexone). What continues is a
goal to promote assessment and treatment that is individualized, person centered,
and outcome driven rather than program driven and placement centered (6–9).
A survey of all 50 US state authorities conducted for the National
Association of State Alcohol and Drug Abuse Directors (NASADAD) found that
43 states (84%) required the use of standard patient placement criteria (10).
Among the states that require patient placement criteria, approximately two-
thirds require providers to use the ASAM Criteria, and this percentage is
growing. States not using the ASAM Criteria developed their own criteria as
with the Level of Care for Alcohol and Drug Treatment Referral (LOCADTR) in
New York; Rule 25 in Minnesota; state specific level-of-care criteria as in Ohio,
Kentucky, Mississippi, Wisconsin, and Pennsylvania; and other states using
criteria based on the Addiction Severity Index (ASI), Global Assessment of
Individual Needs (GAIN-Q), and Treatment Demand Indicator (TDI) (10). Since
the 2006 NASADAD study, there has not been a formal updated survey on what
states, public and private managed care companies, and payers use the ASAM
Criteria for decisions on authorizing addiction treatment. However, at least four
of the states that had their own criteria have since switched to using the ASAM
Criteria, and currently, at least ten managed care companies representing more
than 45 million covered lives use the ASAM Criteria for utilization review (11).
The U.S. Department of Defense (DoD) has endorsed the ASAM Criteria, and a
national survey of the U.S. Veterans Health Administration (VA) addiction
program leaders reported that 48% were very familiar with the ASAM Criteria
(12). However, full implementation across all DoD and VA systems of care has
not been consistent.
In July 2015, the Centers for Medicare and Medicaid Services (CMS)
announced new opportunities for states to design service delivery systems for
Medicaid beneficiaries with a substance use disorder (SUD). Numerous federal
authorities are offering states the flexibility to implement system reforms to
improve care, enhance treatment, and offer recovery supports for people with
SUD. The ASAM Criteria is mentioned in several places as integral to that
service delivery design (13).
SELECTING APPROPRIATE SERVICES
Evolving Approaches to Treatment Matching

The process of matching patients to treatment services has evolved through at
least four approaches, each with a fundamentally different philosophy (14,15).
Complication-driven treatment gives only cursory attention to the diagnosis
of a SUD. In this approach, rather than actively treating the primary alcohol or
other drug disorder that is causing the patient’s symptoms, only the secondary
complications or sequelae are addressed. The gastritis or bleeding esophageal
varices are controlled, the depression is medicated, fractures are splinted or
pinned, but care for addiction is superficial or nonexistent.
In contrast, diagnosis, program-driven treatment recognizes the primacy of
the SUD, but the diagnosis alone drives the treatment plan, level of care, and
length of stay (LOS), rather than the specific assessed needs of the patient. For
example, even before a comprehensive assessment is completed, patients are
assigned to a fixed LOS outpatient or residential program. In such program-
driven services, patients who ask “How long do I have to be in the program?”
are told a specific number of sessions, weeks or months. Often, the focus is on
compliance with program rules and graduation from the program. For some
patients, services in program-driven treatment are in response to a mandated
referral, policy guidelines, or available funding or benefit structures rather than
placement based on a multidimensional assessment, which defines the next
approach.
In individualized, assessment-driven treatment, service priorities are
identified in the context of the patient’s severity of illness and level of function.
Treatment services are matched to the patient’s needs across a continuum of care
(16). Ongoing assessment of progress and treatment response influences further
service recommendations and length of treatment. This individualized treatment
cycle—assessment, treatment matching, level of care placement, and progress
evaluation through multidimensional assessment—represents an approach to
care that much of the addiction treatment field still struggles to fully implement
(15).
Outcome-driven treatment, the most recent approach, adds the element of
measurement of outcomes in real time, so that progress and treatment response is
more explicit and influential. The focus on “during treatment” feedback on both
outcomes and patient engagement and therapeutic alliance allows real-time
modification of the treatment plan. Here, decisions about which problems are
prioritized and what changes are made in strategies and level of care are
informed by tracking the most salient outcomes and measures of alliance and
patient engagement (17,18) (Fig. 30-1).
Figure 30-1 Individualized, outcome-driven treatment.
Uses of Placement Criteria

Placement criteria are irrelevant to the first two approaches to patient placement
(complication-driven and program-driven treatment). In the latter two
approaches, the ASAM Criteria play an integral role by providing a
multidimensional assessment structure, initially to generate a service plan that
leads to appropriate placement and then a formal treatment plan that meets the
patient’s assessed needs and improves the prospects for a positive outcome once
in treatment. The ASAM Criteria also provide nomenclature and guidelines to
describe an expanded set of treatment options and to promote the use of a wide
continuum of services. The ASAM Criteria thus are intended to increase access
to care, enhance the efficient use of limited resources, and improve outcomes
through individualized, assessment-driven treatment and the flexible use of a
broad continuum of care.
Increasingly, however, treatment must be driven not only by the assessment
but more importantly by the outcome of treatment measured in real time. No
single treatment is appropriate for all individuals at all times (19). Therefore,
matching treatment settings, interventions, and services to each individual’s
particular problems and needs is critical to his or her ultimate success in
returning to productive functioning in the family, workplace, and society.
Measurement during treatment that tracks real-time outcomes and the quality of
the patient’s engagement and therapeutic alliance allows for modification of the
strategies and level of care, depending on patient progress or lack thereof
(20,21).
The Concept of “Unbundling”

At present, most addiction treatment services are “bundled,” meaning that a
number of different services are packaged together and paid for as a unit.
However, there has been recognition for some time that clinical services can be
and often are provided separately from recovery environment supports (22).
Unbundling is a practice that allows any type of clinical service (such as
psychiatric consultation) to be delivered in any setting (such as a residential
program) or, for example, partial hospitalization combined with supportive
living instead of residential care for those patients who are not in imminent
danger. With unbundling, the type and intensity of treatment are based on the
patient’s needs and not on limitations imposed by the treatment setting. The
unbundling concept thus is designed to maximize individualized care, to reduce
costs, and to encourage the delivery of necessary treatment in any clinically
feasible setting.
A transition to unbundled treatment often requires systems change in state
program licensure and reimbursement. In terms of treatment, there are no longer
“programs” but rather a constellation of services to meet the needs of each
patient. The systems currently in use for program licensure or accreditation,
billing, reimbursement, and funding would not support unbundled treatment.
However, the ASAM Criteria encourage exploration of unbundling by
suggesting ways to match risk and severity of needs with specific services and
intensity of treatment.
To assist clinicians and programs to advance this approach, the ASAM
Criteria include the Matrix for Matching Severity and Level of Function with
Type and Intensity of Services, which provides benchmarks to determine the
level of risk in each dimension on a scale of 0-4, the needed services, and the
relevant intensity and level of care. The Matrix format has been applied to
Dimensions 1 and 5, acute intoxication and/or withdrawal potential and relapse,
continued use, or continued problem potential, respectively, to guide
pharmacotherapies for alcohol use disorders (23).
UNDERSTANDING THE ASAM
CRITERIA
Four features characterize the ASAM Criteria: (a) comprehensive, individualized
treatment planning, (b) ready access to services, (c) attention to multiple
treatment needs, and (d) ongoing reassessment and modification of the plan.
Functionally, the criteria are used to match services, interventions, and
treatment settings to each individual’s particular problems and (often-changing)
treatment needs as well as his or her strengths, skills, and resources. The ASAM
Criteria advocate for individualized, assessment-driven treatment and the
flexible use of services across a broad continuum of care.
The criteria also advocate for a system in which treatment is readily
available, because patients are lost when the treatment they need is not
immediately available and readily accessible. By expanding the criteria to
incorporate more use of outpatient care, especially for those in early stages of
readiness to change; expanding to five levels of withdrawal management; and
encouraging flexible lengths of stay, the ASAM Criteria are designed to assist in
reducing waiting lists for residential treatment and thus improve access to care.
The criteria are based on research findings that effective treatment attends to
multiple needs of each individual, not just his or her alcohol or other drug use.
To be effective, treatment must address any associated medical, psychological,
social, vocational, legal, and recovery environment problems (19). Through its
six assessment dimensions, the ASAM Criteria underscore the importance of
multidimensional assessment and treatment. To engage the patient in a
collaborative therapeutic alliance, the assessment is in the service of what the
patient wants that will engage them in treatment; for example, “Get my children
back” (17,21). It serves to identify obstacles and resources and liabilities and
strengths within each of the assessment dimensions (Fig. 30-2).
Figure 30-2 Decision tree to match assessment and
treatment/placement assignment. DSM, Diagnostic and
Statistical Manual of Mental Disorders, American Psychiatric
Association; LOF, level of function; ASAM, American
Society of Addiction Medicine Criteria. (International
Statistical Classification of Diseases and Related Health
Problems. World Health Organization/Diagnostic and
Statistical Manual of Mental Disorders. American Psychiatric
Association, 2013:124.)
Objectivity
The criteria are as objective, measurable, and quantifiable as possible. Certain
aspects of the criteria require subjective interpretation. In this regard, the
assessment and treatment of substance-related and addictive disorders are no
different from biomedical or psychiatric conditions in which diagnosis or
assessment and treatment are a mix of objectively measured criteria and
experientially based professional judgments.
Principles Guiding the Criteria

Individualized Treatment Plan
Effective treatment is tailored to the needs of the individual and guided by an
individualized treatment plan that is developed in collaboration with the patient
(17,19,21). Such a plan is based on the patient’s goals for treatment and a
comprehensive biopsychosocial assessment of the patient and, when possible, a
comprehensive evaluation of the family as well (19).
The ASAM Criteria promotes patient-centered care where treatment plans
list problems prioritized by obstacles to treatment and risks and to be arranged
according to severity (such as obstacles to recovery, knowledge or skill deficits,
dysfunction, or loss), strengths (such as good peer refusal skills, a positive social
support system, and a strong connection to a source of spiritual support), goals (a
statement to guide realistic, achievable, short-term resolution of problems or
attainment of positive outcomes), objectives, methods or strategies (what the
patient will do, the treatment services to be provided, the site of those services,
the staff responsible for delivering treatment), and a timetable for follow-through
with the treatment plan that promotes accountability (6).
Recognizing that “an individual’s treatment and services plan must be
assessed continually and modified as necessary to ensure that it meets his or her
changing needs” (19), the plan is written to facilitate measurement of progress.
As with other disease processes, the length of service is linked directly to the
patient’s response to treatment (eg, attainment of the treatment goals and degree
of resolution of the identified clinical problems) rather than a predetermined
time frame based on the length of the treatment program or available
reimbursement (6).
Choice of Treatment Levels

Referral to a specific level of care must be based on a careful assessment of the
patient. The goal that underlies the criteria is the placement of the patient in the
most appropriate level of care. For both clinical and financial reasons, the
preferred level of care is the least intensive level that meets treatment objectives
while providing safety and security for the patient. Moreover, while the levels of
care are presented as discrete levels, in reality, they represent benchmarks or
points along a continuum of treatment services that could be used in a variety of
ways, depending on a patient’s needs and response. A patient could begin at a
more intensive level and move to a more or less intensive level of care,
depending on his or her individual needs and progress in treatment. For patients
who have been previously treated and have relapsed, the choice of the current
level of care should be based on an assessment of the patient’s history and
current functioning, not automatic placement in a more intensive level of care.
Such placement by policy assumes that relapse after treatment indicates that the
previous level of care was of insufficient intensity. In fact, poorly matched
services may have been the problem, for example, recovery and relapse
prevention services for a patient at an early stage of change who needs
“discovery” motivational enhancement services (6,24).
Continuum of Care
In order to provide the most clinically appropriate and cost-effective treatment
system, a continuum of care must be available. Such a continuum may be offered
by a single provider or multiple providers. For the continuum to work most
effectively, it is best distinguished by three characteristics: (a) seamless transfer
between levels of care, (b) philosophical congruence among the various
providers of care, and (c) timely arrival of the patient’s clinical record at the next
provider. It is most helpful if providers envision admitting the patient into the
continuum through their program rather than admitting the patient to their
program.
Many providers of treatment services offer only one of the many levels of
care described. In such situations, movement between levels might mean
referring the patient out of the provider’s own network of care. While lack of
reimbursement for some levels of care or lack of availability of other levels of
care may render this impossible at present, the goal of these criteria is to
stimulate the development of efficient and effective services with attendant
funding or reimbursement that can be made available to all patients.
Progress Through the Levels of Care

As a patient moves through treatment in any level of care, his or her progress in
all six dimensions should be continually assessed. Such multidimensional
assessment ensures comprehensive treatment. In the process of patient
assessment, certain problems and priorities are identified as justifying admission
to a particular level of care. The resolution of those problems and priorities
determines when a patient can be transferred to a different level of care or
discharged from treatment. The appearance of new problems may require
services that can be effectively provided at the same level of care or that require
a more or less intensive level of care.
Each time the patient’s response to treatment is assessed, new priorities in
the treatment plan are identified. The intensity of the services and strategies
incorporated in the treatment plan helps to determine the most efficient and
effective level of care that can safely provide the care articulated in the
individualized treatment plan. Patients may, however, worsen or fail to improve
in a given level of care or with a given type of program. When this happens,
changes in the level of care or program should be based on a reassessment of the
treatment plan, with modifications to achieve a better therapeutic response. This
may result in a decision to transfer the patient to another level of care or different
type of treatment (6).
Should a patient drink or use other drugs during treatment, the immediate
response should be to assess reasons for a poor outcome and revise the treatment
plan rather than automatically change the level of care or administratively
discharge the patient. Additionally, some benefit managers require that a patient
be “motivated for sobriety” as a requirement for admission to a program. Given
the characteristic signs of ambivalence and lack of readiness to change of
addiction disorders, the only requirement should be that the patient is willing to
enter treatment. Clinicians then facilitate the patient’s self-change process along
the stages of change using motivational enhancement strategies.
Length of Stay (LOS)

The LOS or service is determined by the patient’s progress toward achieving his
or her treatment plan goals and objectives. Fixed LOS or program-driven
treatment is not individualized and does not respond to the particular problems
of a given patient. While fixed LOS programs are more convenient and
predictable for the provider, they may be less effective for individuals (19).
Clinical Versus Reimbursement Considerations

The ASAM Criteria describe a wide range of levels and types of care. Not all of
these services are available in all locations, nor do all payers cover them.
Clinicians who make placement decisions are expected to supplement the criteria
with their own clinical judgment, their knowledge of the patient, and their
knowledge of the available resources. The ASAM Criteria are not intended as a
reimbursement guideline, but rather as a clinical guideline for making the most
appropriate placement recommendation for an individual patient with a specific
set of symptoms and behaviors. If the criteria only covered the levels of care
commonly reimbursable by private insurance carriers, they would tacitly endorse
inappropriate care by limiting recommendations for the complete continuum of
care.
”Treatment Failure”
Two incorrect assumptions are associated with the concept of “treatment
failure.” The first is that the disorder is acute rather than chronic, so that the only
criterion for success is total and complete cure and elimination of the problem.
Such expectations are recognized as inappropriate in the treatment of other
chronic disorders, such as diabetes, asthma, or hypertension. No one expects that
simply because a patient has been treated on one occasion for asthma, there will
never be another episode. The same recognition of chronicity should be applied
to the treatment of addiction, for which appropriate criteria would involve
reductions in the intensity or severity of symptoms, the duration of symptoms,
and the frequency of symptoms.
The second assumption is that responsibility for treatment “failure” always
rests with the patient (as in, “the patient was not ready”). However, poor
treatment outcomes also may be related to a provider’s failure to provide
evidence-based services tailored to the patient’s needs.
Finally, there is a concern that some benefit managers require that a patient
“fail” at one level of care as a prerequisite for approving admission to a more
intensive level of care (eg, “failure” in outpatient treatment as a prerequisite for
admission to inpatient treatment). In fact, such a requirement is no more rational
than treating every patient in an inpatient program or using a fixed LOS for all.
Such a strategy potentially puts the patient at risk because it delays care at a
more appropriate level of treatment and potentially increases healthcare costs if
restricting the appropriate level of treatment allows the addiction disorder to
progress.
The ASAM Criteria and State Licensure or

Certification
The ASAM Criteria contain descriptions of treatment programs at each level of
care, including the setting, staffing, support systems, therapies, assessments,
documentation, and treatment plan reviews typically found at that level. This
information should be useful to providers who are preparing to serve a particular
group of patients, as well as to clinicians who are making placement decisions.
Nevertheless, the descriptions are not requirements and are not intended to
replace or supersede the relevant statutes, licensure, or certification requirements
of any state.
ASSESSMENT DIMENSIONS
The ASAM Criteria identify six assessment areas (dimensions) as the most
important in formulating an individualized treatment plan and in making
subsequent patient placement decisions. Table 30-1 outlines the six dimensions
and the assessment and treatment planning focus of each dimension.
TABLE 30-1 ASAM Criteria Assessment Dimensions

With increased focus on recovery and strength-based, person-centered
assessments and services, a multidimensional assessment should address not
only a patient’s needs, obstacles, and liabilities but also his or her strengths,
skills, resources, and supports to promote recovery. For example, in assessing a
patient’s relapse, continued use, or continued problem potential (Dimension 5),
the focus should not restrict inquiry to cravings, peer refusal skill problems,
relapse triggers, or other impulses but also to identification of any periods of
sobriety or mental health wellness and what skills and resources produced a
good outcome. Even if these were for relatively short periods of time,
assessment of how the patient changed attitudes, knowledge, skills, or behavior
to achieve success identifies strategies that can be included in the individualized
service plan.
Similarly, if a person has been suicidal before, but has never needed
hospitalization or medical care for serious cutting or overdose behavior, this may
suggest a level of impulse control that can be harnessed in the emotional,
behavioral, or cognitive (Dimension 3) part of the treatment plan. Or if a patient
is homeless but has one family member who is still invested in the patient’s well-
being, that family member is a recovery support (Dimension 6) who should be
involved in the patient’s treatment.
Interactions Across Dimensions in Assessing

for Level of Care
While the ASAM Criteria assesses individuals in each dimension independently,
it also recognizes the importance of the interaction across dimensions. Such
interaction is explained in “Determining Dimensional Interaction and Priorities”
(6). For example, when assessing an individual for severity, a history of
moderate or severe withdrawal without any current intoxication or withdrawal or
current intoxication without a history of significant withdrawal problems should
generate a lesser level of concern than a combination of a history of moderate or
severe withdrawal with current symptoms of intoxication or withdrawal.
In reality, there is considerable interaction across dimensions. For example,
significant problems with readiness to change (Dimension 4), coupled with a
poor recovery environment (Dimension 6) or moderate problems with relapse or
continued use (Dimension 5), may increase the risk of an acute exacerbation of
addiction. Another commonly seen combination involves problems in
Dimension 2 (such as chronic pain that distracts the patient from the recovery
process) coupled with problems in Dimensions 4, 5, or 6.
The converse also is true. For example, problems with relapse potential
(Dimension 5) may be offset by a high degree of readiness to change (Dimension
4) or a very supportive recovery environment (Dimension 6). The interaction of
these factors may result in a lower level of severity than is seen in any dimension
alone (6).
The lesson here is that assessments are most accurate when they take into
account all of the factors (dimensions) that affect each individual’s receptivity
and ability to engage in treatment at a particular point in time.
Continued Service and Transfer/Discharge

Criteria
The ASAM Criteria, since the first edition in 1991, have consistently indicated
that the duration of treatment varies with the severity of the individual’s illness
and his or her response to treatment. Thus, fixed LOS programs are not
consistent with individualized, person-centered, and outcome-driven treatment.
Patients, especially individuals mandated to treatment, in fixed LOS programs
often focus more on “doing time” rather than “doing treatment” where improved
outcomes determine LOS and level of care, not the mandated LOS. The
continued service and transfer/discharge criteria thus play a prominent role in
guiding when a patient should continue in the current level of care or when their
progress and outcome in treatment warrants transfer or discharge to a different
type and/or level of service.
The assessment process for continued service or transfer/discharge is the
same as for admission, with the reassessment of multidimensional severity
determining the treatment priorities, intensity of needed services, and the
decision about ongoing level of care. Decisions concerning continued service,
transfer, or discharge involve review of the treatment plan and assessment of the
patient’s progress. That is, they require the same type of multidimensional
assessment process that led to admission to the current level of care (6).
LEVELS OF CARE
The ASAM Criteria conceptualize treatment as a continuum marked by five
basic levels of care, which are numbered from levels 0.5 through level 4. Thus,
the ASAM Criteria provide the addiction field with a nomenclature for
describing the continuum of addiction services, as follows:
Level 0.5: early intervention

Level 1: outpatient services
Level 2: intensive outpatient/partial hospitalization services
Level 3: residential/inpatient services
Level 4: medically managed intensive inpatient services
Within each level, a decimal number (ranging from 0.1 to 0.9) expresses
gradations of intensity within the existing levels of care. This structure allows
improved precision of description and better “interrater” reliability by focusing
on five broad levels of care. Thus, the ASAM Criteria describe gradations within
each level of care. For example, a 2.1 level of care provides a benchmark for
intensity at the minimum description of level 2 care. There are also five levels of
withdrawal management in the adult criteria to allow a seamless continuum for
withdrawal management, rather than a predominantly intensive and expensive
emphasis on acute or subacute inpatient withdrawal management. For more
details on each of the levels of care within the broad levels of care, see Table 30-
2.
TABLE 30-2 ASAM Criteria Levels of Care

ASAM, American Society of Addiction Medicine Criteria.
PLACEMENT DILEMMAS
Even those using the ASAM Criteria regularly encounter “real-world” dilemmas
surrounding access, reimbursement, funding, resource allocation, and
availability of services, particularly for patients with co-occurring medical or
psychiatric conditions.
Co-occurring Disorders
When the first edition of the ASAM Criteria was published in 1991, the criteria
were designed for programs that offered only addiction treatment services.
However, even that early edition also acknowledged that some patients come to
treatment with physical health (Dimension 2) and psychiatric (Dimension 3)
disorders that coexist with their addiction-related problems. Clinical reality
suggests that programs and practitioners who are committed to meeting the total
needs of the patients they serve must be able to meet the needs of people with
co-occurring and complex disorders, either directly or through referral or
consultation. This concept is particularly relevant today, as the range of patient
needs and clinical variability continues to broaden.
Factors contributing to this clinical reality include the expansion of
substance use and substance-induced disorders in younger populations; greater
sensitivity to substance use and addiction problems in the mental health, welfare,
and criminal justice systems; greater awareness of the role of trauma in
addiction; and increased commitment to earlier intervention in addiction in
preference to fragmented services and incarceration. A major factor has been the
growing body of scientific evidence pointing to addiction as a disease of the
brain; another is the development of pharmacotherapies for addiction. Greater
understanding of the uses and effects of psychosocial and cognitive–behavioral
strategies also has heightened awareness of a broadened range of modalities to
meet individual needs.
The ASAM Criteria thus incorporate criteria that address the large subset of
individuals who present for treatment with co-occurring SUDs and co-occurring
mental disorders. Table 30-3 summarizes what kinds of patients with co-
occurring mental and substance-related disorders are best treated in two kinds of
programs: co-occurring capable and co-occurring enhanced services. Since co-
occurring disorders are so prevalent, the ASAM Criteria encourage all programs
to be at least co-occurring capable (Table 30-4).
TABLE 30-3 Matching Patients With Co-occurring

Disorders to Services
TABLE 30-4 Application of the ASAM Criteria to
Clinical Presentations
Assessment of Imminent Danger
Residential treatment has often been used for patients with chronic relapse
problems, those with poor recovery environments, those who are homeless, and
those in need of motivational strategies to “break through denial.” In the ASAM
Criteria, residential treatment is reserved for stabilization of those in imminent
danger. Such patients need a residential program that offers clinical staff and
services 24 hours a day in order to respond to the patient’s issues that pose the
imminent danger, that is, that there is a strong probability certain behaviors such
as continued use will occur, that such behaviors will present a significant risk of
adverse consequences to the individual and/or others, and that such adverse
events will occur in the very near future (6).
Mandated Level of Care or Length of Service

In some cases, an individual is referred for treatment at a specific level of care
and/or for a specific length of service (eg, an offender in the criminal justice
system may be given a choice of a prison term or a fixed LOS in a treatment
center). Such mandated or court-ordered referrals may not be based on clinical
considerations and thus may be inconsistent with a placement decision arrived at
through the ASAM Criteria. In such a case, the provider should make reasonable
attempts to have the order amended to reflect the assessed clinical level or length
of service.
If the court order or other mandate cannot be amended, the individual may
be continuing treatment at a level of care or for an LOS more intense than is
clinically indicated. The patient’s readiness for discharge or transfer and the
staff’s attempts to implement a clinically appropriate placement should be noted
in the clinical record, and the treatment plan should be updated in a manner that
provides the patient with the opportunity to continue the recovery process at the
same level of care even though it could be continued at a less intensive level of
care.
Logistical Impediments
Logistical problems can arise anywhere but are found most frequently in rural
and underserved inner-city areas. When logistical considerations are an
impediment to the indicated services (eg, lack of available transportation is a
barrier to a patient’s access to an indicated outpatient program), an outpatient
service combined with unsupervised/minimally supervised housing may be an
appropriate treatment intervention. In cities or towns, such a domiciliary option
might be found in a group living situation (such as a Salvation Army program,
motel accommodations, YMCA/YWCA, or mission). In rural and other
underserved areas, options could include (a) the creation of a supervised housing
situation by using unused treatment beds, (b) assertive community treatment
models in which the treatment is brought to rural areas (such as Native American
settlements) and provided in weekend intensive models at sites such as
community centers and churches, (c) vans that are sent out to pick up patients
and bring them to a treatment site, and (d) using a van or motor home as an
office or group therapy room.
The Need for a Safe Recovery Environment

When a patient lives in an environment that is so toxic as to preclude recovery
efforts (as through victimization or exposure to an actively addicted person) and
a level 1 or 2 outpatient service is indicated, the patient may need referral to a
safe place to live while in treatment, as well as to treatment itself. One example
might be combining a women’s shelter with a level 2.1 or 2.5 treatment program.
Assuring Individualized Treatment

Many programs claim to provide individualized care, but how can quality
auditors know that such care actually is provided? There are at least three
efficient ways to determine whether a program is providing truly individualized
treatment:
1. Take 10 closed clinical case records and compare the treatment plans. If the
reviewer cannot clearly distinguish patients by their treatment plans, the
treatment is not individualized.
2. Review the progress notes, and determine whether they relate back to the
objectives or strategies in the treatment plan.
3. For programs that receive reimbursement from multiple payers, compare
lengths of service by sources of payment. If the lengths of stay correspond
to payer type, then the program is payment driven rather than offering
individualized treatment.
Fidelity to the Spirit and Content of the

ASAM Criteria
The following implementation issues suggest that clinicians and programs still
struggle with understanding the full intent of the ASAM Criteria:
1. Programs that describe their services as a fixed LOS program as evidenced

by description of the program as a “30-day inpatient program” or “24-
session IOP.” Or if the program claims no fixed LOS, check what clients
say if you ask: “How long do you have to be here?” An answer involving
fixed numbers of sessions or weeks reveals regression to a program-driven
model.
2. Language used: “extended residential”—LOS should be determined by
severity, function, and progress, not a priori that the patient needs extended
LOS in a residential setting; “graduate” and “complete the program” reveal
a focus on a fixed plan and program rather than on functional improvement
as the determinant of level of care.
3. Waiting lists for residential when admission criteria require “imminent
danger.” If a patient is stable enough to safely await a residential bed, then,
by definition, the person is not in imminent danger needing 24-hour
residential treatment.
4. States and counties that fund only a few levels of care, which discourages a
seamless continuum of care; licensure and contractual arrangements that
keep levels of care in fixed programs that discourage flexible overlapping
of levels, for example, a state may contract only for level 3.7-WM, which
forces the program to staff for and document on every patient as if they are
continually a 3.7-WM severity, when that may change in 2 days.
5. Levels of withdrawal management available are often only 4- or 3.7-WM,
which drives up cost and allows only brief LOS in high-intensity settings.
This leads to rapid return to substance use when the patient’s withdrawal
has not been fully managed. An ambulatory or residential level might be
both more clinically appropriate and less costly. Use of the five levels of
withdrawal management would allow longer LOS for the same or fewer
financial resources.
Exceptions to the Patient Placement Criteria

In making treatment placement decisions, three important factors override the
patient–treatment match with regard to levels of care:
1. Lack of availability of appropriate, criteria-selected care.

2. Failure of a patient to progress at a given level of care, so as to warrant a
reassessment of the treatment plan with a view to modifying the treatment
approach. Such situations may require transfer to a specialized program at
the same level of care or to a more intensive or less intensive level of care
to achieve a better therapeutic response.
3. State laws regulating the practice of medicine or licensure of a facility that
require the use of different criteria.
Unique clinical presentations or extenuating circumstances require some

flexibility in application of the criteria to ensure the safety and welfare of the
patient.
Gathering Data to Improve Systems of Care

There are no ideal systems of care that have seamless levels of care and where
all policy, licensure, and funding obstacles have been removed. Clinicians should
resist the impulse to immediately place a patient in what is locally available and
pragmatic. If sufficient multidimensional assessment reveals that an
appropriately matched level of care is not available, this provides an opportunity
to gather data to assist in systems change. It would take 30 seconds to note on a
form the date and patient’s name and case number, fill in the level of care or
service clinically indicated and the level of care or service actually received, and
then note the particular reason(s) for the difference in your region and the
consequences of such a mismatch. These data can identify the greatest gaps in
services and prioritize where resources need to be concentrated to improve the
system of care (Table 30-5).
TABLE 30-5 Data Gathering on Discrepancy Between

Needed and Available Services: Placement Summary
Mee-Lee D, Shulman GD, Fishman MJ, et al., eds. The ASAM Criteria: Treatment Criteria for Addictive,
Substance-Related, and Co-Occurring Conditions. 3rd ed. Carson City, NV: The Change Companies,
2013:126.
RESEARCH ON THE ASAM CRITERIA

The ASAM Criteria are the most intensively studied set of addiction placement
criteria. Scientists began the crucial process of testing the ASAM Criteria in the
early 1990s to develop decision rules through an international system of data
gathering, quantitative analysis, and empirical feedback (26).
In the intervening decades, dozens of reports published in the peer-reviewed
literature have been supported by over 7 million dollars of US government
funding. Project funding came from the National Institute on Drug Abuse and
the National Institute on Alcohol Abuse and Alcoholism and the Center for
Substance Abuse Treatment of the Substance Abuse and Mental Health Services
Administration (26). Consultation or training projects were funded by Aetna
Behavioral Health, Harvard Business School, the Oklahoma Department of
Mental Health and Substance Abuse Services, and the U.S. Veterans
Administration. Additional studies were subsequently supported by the federal
governments of Belgium and Norway. Research training fellowships have been
funded by the World Health Organization and Israel, and scientific review
conferences have been conducted in Iceland and Switzerland.
A considerable body of work exists to date on the ASAM Criteria including
at least ten evaluations involving a total of 3672 adult subjects (27). Studies have
included patients with a variety of SUDs and have examined a variety of time
periods, including immediate dropout, 1-month, 3-month, and 1-year. Controlled
studies have found that treatment based on the ASAM Criteria versus ASI-based
and clinician-based placement approaches is associated with a variety of
outcomes, including better initial engagement, better retention, reduced
substance use, less morbidity, better client functioning, and more efficient
service utilization than mismatched treatment (26,28–33).
It should be noted that there are separate ASAM Criteria sets for adults and
adolescents. Adolescents are also receiving research attention using these criteria
(34), which appear to be the most widely used treatment planning approach for
highly rated adolescent treatment programs (35). Adolescents were studied in a
pilot comparing two matched adolescent residential (Level 3) programs; better
clinical outcomes were found in the program that used regular patient
assessment and treatment plan adjustment according to the ASAM dimensions
(36).
Given the clinical complexity that is codified in the ASAM Criteria decision
logic, standardization is an important goal for the field—particularly in the era of
health information technology and payment reform. One study tried to evaluate
two different automated ASAM-related software approaches, based on an
enhanced ASI. Patients completing an intake ASI (N = 2429) in 78 addiction
treatment programs in Arkansas, New Hampshire, Rhode Island, and Utah were
naturalistically given level of care (LOC) assignments based on availability and
clinical considerations. Two placement recommendations were independently
calculated: using either ASI summary score thresholds or an algorithm
approximating the ASAM Criteria. Using treatment completion and self-reported
abstinence at 6 months post discharge as outcomes, both approaches showed
evidence of predictive validity. Patients who were undertreated, meaning that
they were placed in a level of care less intense than recommended according to
the matching calculations, did consistently worse on both outcomes and
generally significantly so. However, results were not as consistent with regard to
overmatching, meaning when patients were placed in a level of care more
intensive than recommended by matching calculations (29).
These results support the predictive validity and effectiveness (improved
outcomes for ASAM dimension-matched adolescents; worse outcomes for
undermatched adults) of the use of Patient Placement Criteria (PPC) (research
was conducted on previous editions named “ASAM Patient Placement Criteria”
for what is now in the 2013 edition just “The ASAM Criteria”). They also
indicate that the Patient Placement Criteria provide valid clinical decision-
making guidelines and have good feasibility and reliability through standardized
computer assessment instruments and good concurrent validity in treating
patients throughout the multidimensional assessments (37). Undertreatment has
been found to be clinically adverse in multiple studies (31,32,38). Overtreatment
also causes difficulties, including unnecessary and expensive treatment. In one
study of 281 patients, the majority (59%) was overtreated (placed in a level of
care more intensive than indicated by ASAM Criteria), and the reason for 93%
of these was because Medicaid covered residential care (39). Two controlled
studies found that overtreatment is not simply a financial waste—it can also be
associated with adverse clinical outcomes (40,41). Overall, it is important for
systems to detect, report, and overcome the reasons for such mismatches, which
can include issues of patient choice, payer rejection, and limited access. The
various causes of discrepant treatment are systematically gathered when
clinicians use the standardized software application, CONTINUUM—The
ASAM Criteria Decision Engine, permitting research, evaluation, and data-
driven system improvement. Ongoing observational data collected through this
software will inform empiric revisions to the heretofore consensus
recommendations contained within the ASAM Criteria.
THE ASAM CRITERIA SOFTWARE

Technology is poised to dramatically advance the ASAM Criteria. The PPC-1–
based computerized research algorithm of Gastfriend et al. at Massachusetts
General Hospital proved that the ASAM Criteria can be standardized to achieve
good interrater reliability (42). This is an important contributor to validity, which
was subsequently demonstrated in several observational studies
(30,32,33,38–44). A new software product was authorized by ASAM and was
designed to implement every admission decision rule of the ASAM Criteria
updated text (ie, PPC-2R and the 2013 editions), to be user-friendly, and to serve
as the authorized, standard implementation, internationally. After translation into
Norwegian and use in 10 treatment programs across Norway over 3 years, this
software showed good convergent and predictive validity and also received high
satisfaction ratings from both patients and counselors (41,45,46). In Uzbekistan,
translated into both Uzbek and Russian, use of the PPC-2R software reportedly
increased individualization of placements compared with the mandated treatment
that was not based on an individualized assessment (47). Using Dutch and
French translations, 201 Belgian patients who received matched or a more
intensive level of care had significantly better 30-day global outcomes than
patients who were mismatched to a less intensive level of care than
recommended (33).
The PPC-2R software has been updated to become CONTINUUM
incorporating the changes of the third edition of The ASAM Criteria (6).
SAMHSA, the Substance Abuse and Mental Health Services Administration,
and ASAM’s technology partners supported the updating of the software with
nearly a million dollars of investment to prepare the software for integration into
electronic health records for the Health Information Technology Act, the federal
Parity Act, healthcare reform, and new rules allowing states flexible waivers to
create new payment models for Medicaid.
This new software presents the opportunity, for the first time, to permit both
providers and researchers throughout the field to speak the same language and
arrive at the same LOC determinations. The software includes the additional
feature of confidential data uploads to an ASAM-authorized National Addiction
Patient Registry, which is facilitating aggregate analyses of patient placements,
service utilizations, and clinical outcomes. This Registry has two simultaneous
benefits for the field. It will permit treatment programs to understand their
utilization patterns and needs. At the same time, the data repository will offer
research centers a precise, objective look at the validity of the ASAM Criteria.
In 2014, 20 addiction treatment systems across the United States used
CONTINUUM in a 6-month National Demonstration Project. This project
reported good adoption by participating programs, acceptance by intake
clinicians, and satisfaction among patients. CONTINUUM subsequently
underwent commercial release throughout the United States, with large initial
pilots by county and state systems, overseen by the Coalition for National
Clinical Criteria, which represents major provider, professional, and government
agencies and organizations supportive of the ASAM Criteria. Such mechanisms
permit ongoing improvement of the ASAM Criteria. The result is that patients
will benefit not only from the art of addiction medicine, for example, ASAM’s
expert consensus, but by the science as well—driven by quantitative, empirical
data.
CONCLUSIONS
Four important missions underlie the ASAM Criteria: (a) to enable patients to
receive the most appropriate and highest quality treatment services, (b) to
encourage the development of a broad continuum of care, (c) to promote the
effective and efficient use of care resources, and (d) to help protect access to and
funding for care. The use of placement criteria in treatment planning thus
represents far more than a narrow utilization review or case management
process. Correctly applied and implemented in a nationally standardized system,
the ASAM Criteria can assist patients in receiving much greater lengths of
professional care for the same or less resources spent now on just one or two
levels of care. For example, withdrawal management provided in just hospital
Level 4-WM (Medically Managed Inpatient Withdrawal Management) or Level
3.7-WM (Medically Monitored Inpatient Withdrawal Management) albeit for
short lengths of stay of 3 or 4 days uses as much resources if not more, than
individualized treatment across all five levels of withdrawal management
(Levels 1-, 2-, 3.2-, 3.7- and 4-WM). One day in Level 4-WM is equivalent in
cost to 5-6 days in Levels 2 or 3.2-WM. This allows for longer lengths of stay
for withdrawal management as the diminishing severity of withdrawal is
matched to the needed intensity of WM services in a continuum of WM levels
instead of just 1 or 2 levels.
Effective implementation of the ASAM Criteria will require modernizing
technology, as has already been undertaken elsewhere in health care, and a shift
in thinking toward outcome-driven case management. A variety of treatment
agencies will need to make this shift, including regulatory agencies, clinical and
medical staff, and referral sources, such as courts, probation officers, child
protective services, employers, and employee assistance professionals (48). The
ASAM Criteria and its software implementation offer a system for improving
patient-centered, collaborative care through the use of multidimensional
assessment and treatment planning that permits more objective evaluation of
patient outcomes. With improved outcome analysis driving treatment decisions,
the problem of access to care and funding of treatment can be championed more
effectively.
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CHAPTER 31
Linking Addiction Treatment With
Other Medical and Psychiatric
Treatment Systems
Karran A. Phillips, Peter D. Friedmann, Richard Saitz,
and Jeffrey H. Samet
CHAPTER OUTLINE
Introduction
Potential Benefits of Linked Services
Barriers to Optimal Linkage
Models of Linked Services
Prospects for Improved Linkage
INTRODUCTION
Persons with substance use disorders are at substantial risk for coexisting
medical and mental health problems and often present to medical and mental
health settings. Similarly, patients in addiction treatment commonly experience
medical and psychiatric problems, which can increase relapse risk (1–3). In both
medical and addiction treatment settings, the provision of comprehensive care
for individuals with substance use disorders presents challenges to clinicians
who traditionally have focused only on issues reflecting their own training and
perspectives. For example, medical practitioners typically address the toxic
effects of a particular substance, such as seizures from benzodiazepine
withdrawal or cirrhosis from alcohol use, or the health consequences of high-risk
behaviors, such as viral hepatitis or HIV. Psychiatrists and other mental health
professionals focus on the mental health issues that are prevalent among patients
with substance use disorders. Meanwhile, addiction specialists may focus on the
individual’s destructive preoccupation with obtaining and consuming a
psychoactive substance and the negative consequences of such actions. For the
patient, these issues are inseparable and often interrelated, yet many clinicians
operate in distinct systems of care, each with its own—often exclusive—focus.
For example, the medical literature contains instances of medical practitioners
not attending to their patients’ addiction by failing to recognize or be aware of
treatments being received, screen, intervene, or refer (4–6). Similarly, patients in
addiction treatment programs report unmet psychological and medical needs
(7,8). Patients with substance use disorders and psychiatric or medical illnesses
are sometimes bounced between systems and given contradictory
recommendations that can lead to continued substance use or that can be
dangerous—told that they must be abstinent before they can receive treatment
for their psychiatric and medical problems, that they cannot receive treatment if
they are taking particular medications, or that they are too sick (medically or
psychiatrically) to get into an addiction treatment program—resulting in a
clinical “Catch-22.”
Patients who present with complex, interrelated, comorbid problems make
apparent the disconnection between these parallel yet often separate systems of
care. Healthcare reform building on the Mental Health Parity and Addiction
Equity Act (MHPAEA) of 2008 (9) such as the Patient Protection and Affordable
Care Act (10) includes addiction as an “essential health benefit” and increased
the number of individuals with addiction presenting to primary care and other
healthcare settings (11,12). The establishment of the new subspecialty of board-
certified physicians in addiction medicine joining the ranks of addiction
psychiatry physicians will greatly help to close some of these gaps. However,
given that many systems still lack access to certified addiction physicians (13),
further training of generalist clinicians about addiction issues and their
acceptance to take on role responsibility for addiction care, and linkages across
the systems of medical, mental health, and addiction care will be needed to
improve the quality of care delivered to patients with addiction (14). This
chapter reviews the potential benefits of linkages between primary medical care,
mental health, and addiction services; identifies the potential barriers to such
linkages; and describes published linkage models.
POTENTIAL BENEFITS OF LINKED

SERVICES
Effective linkage may benefit individuals with substance use in the following
common scenarios: when issues related to use and addiction are not addressed in
primary care and mental health settings, when medical and mental health issues
are not addressed in addiction treatment, and when the patient is seen in two or
more of these settings but no effective communication between or within the
systems occurs.
From a patient’s perspective, the potential for improved overall care is the
motivating force for linkage of systems (Table 31-1). For example, a patient
receiving methadone who is prescribed efavirenz, which can decrease
methadone blood levels, without coordination of care might experience
withdrawal symptoms, toxicity, provider unease about possible methadone
diversion, or relapse. Chronic pain and pain-related dysfunction are common in
primary care with nearly one-third of primary care patients who screened
positive for drug use reporting severe pain and severe pain-related dysfunction
(15). The potential for improved pain control and less substance use in a patient
receiving substance use treatment services is another possible benefit of linked
care. Other possible benefits from such linkages include proper attribution of
side effects of medications (vs. substance use or withdrawal), proper attribution
of symptoms to their causes (eg, cocaine causing uncontrolled hypertension),
and better access to medically assisted withdrawal and treatment for patients in
the medical system. Medical errors are a major preventable cause of harm and
death; uncoordinated care is an important risk for such errors in the realm of
serious medication interactions and treatments at cross-purposes resulting from
clinicians who are unaware. A profound potential benefit of linked systems is the
improved well-being of individual patients in terms of addiction severity,
medical and psychiatric condition severity, and overall quality of life (16,17).
Additional benefits include the provision of convenient, comprehensive, and
coordinated care to patients and the entry of new patients into treatment (18).
Finally, linking services might also decrease stigma, as all clinicians would
acknowledge and support the patient’s efforts toward abstinence and all medical
and psychiatric conditions would be addressed in the same location.
TABLE 31-1 Potential Benefits of Linking Addiction

Treatment With Other Medical and Psychiatric Services
From the perspectives of the primary care clinician and the mental health
clinician, possible benefits of linkage include early identification of and relapse
prevention for substance use disorders (19), increased consideration of alcohol
and drug use conditions in the formulation of differential diagnoses, better
access to addiction treatment services, enhanced patient adherence to
appointments and medications, and improved addiction training and experience
for personnel. From an addiction treatment clinician’s perspective, stronger
linkages could yield improved outcomes of addiction treatment, similar to that
demonstrated with the addition of needed psychosocial services (20,21). Ready
availability of needed medical and mental health services also would allow
addiction professionals to do what they do best: focus on the core substance use
issues. Exposure to examples of successful treatment could reduce stigma on the
part of medical and mental health professionals toward addiction and enhance
their appreciation of the value of addiction treatment. Bringing addiction
treatment closer to mainstream medical care and exposing its similarities to the
care of other chronic illnesses would support the ongoing efforts to implement
parity for addiction treatment. Addiction clinicians could learn about the medical
and mental health complications of addiction and enhance their appreciation of
the patient’s conditions, healthcare needs, and prevention approaches.
Conceivably, the linkage of services could provide an opportunity to affect other
behavior-related issues, such as sexually transmitted diseases (including human
immunodeficiency virus) and smoking. Finally, linkage of services could
enhance quality improvement efforts within addiction treatment systems—as
articulated in an accreditation requirement from the Joint Commission (that
accredits healthcare organizations)
(https://www.jointcommission.org/facts_about_behavioral_health_care_accreditation/
and by the focus of an Institute of Medicine (IOM) report (22)—by taking
lessons from medical settings that have grappled with these issues as part of the
restructuring of medical care systems.
From a societal perspective, stronger linkages might lower long-term costs,
including savings from reduced HIV and hepatitis incidence and other health-
related sequelae of averted substance use, reduced incarceration and other
criminal justice expenditures, and increased productivity (23,24). Other benefits
include reduced duplication of services across these systems. Finally, a potential
public health achievement would be improved health outcomes for specific
populations burdened with the substantial morbidity associated with substance
use disorders.
BARRIERS TO OPTIMAL LINKAGE
Medical Training
Many barriers impede better linkage of services. One well-documented problem
has been the perspective of many medical practitioners that addressing alcohol
and other drug use issues is not providing medical care and thus is outside his or
her purview (25). This viewpoint is changing. Medical education about addiction
was sorely deficient in past years (26). In the mid-1980s, medical students’
suboptimal knowledge, perceived responsibility for caring for patients with
alcohol use disorders, and confidence in clinical skills were related to reported
screening and referral practices; resident physicians perceived even less of a
responsibility for care, had less confidence in their skills, and had more negative
attitudes (27). These reports suggested that curricula needed improvement and
that education, though necessary, may not be sufficient to maintain appropriate
attitudes and practices on the part of physicians. Efforts to rectify that situation
have been under way, most notably in the past two decades, with development of
appropriate standards, curricula (28), and an increasing number of effective
addiction educators within many disciplines. Past efforts by the Health
Resources and Services Administration (HRSA) and the Center for Substance
Abuse Treatment (CSAT) include a goal to have addiction educators in place in
every health professional school in the United States (29–34) and more recently
CSAT support for resident physician training in Screening, Brief Intervention,
and Referral to Treatment (SBIRT) and the creation of the Coalition On
Physician Education in Substance Use Disorders (http://www.cope-assn.org/).
Progress requires time, dedicated resources, attention to continuing medical
education, and maintenance of high-quality care. The American Board of
Medical Specialties (ABMS) officially recognized Addiction Medicine as a
subspecialty in October 2015. ABMS recognition allows physicians from any of
the 24 Member Boards to become board certified in this new subspecialty. It also
allows for accreditation by the Accreditation Council on Graduate Medical
Education for addiction medicine fellowship programs, which will result in an
increased addiction provider workforce and access to care
(http://www.abms.org/news-events/abms-officially-recognizes-addiction-
medicine-as-a-subspecialty/). These efforts were energized by the emergence of
the American Board of Addiction Medicine (ABAM) and the ABAM
Foundation and should continue as addiction medicine physicians work together
with addiction psychiatrists to treat this population and model excellent care to
medical students and residents.
Urada et al. conducted interviews with management, staff, and patients of
five federally qualified health centers (FQHCs) in California involved in
integrating their substance use services within primary care and found, compared
to mental health services, there was a trend for substance use services to be less
integrated with primary care and rated significantly less effective. The perceived
difference in effectiveness appeared to be due to clinician training (35). Medical
clinicians in practice generally report having received minimal training in
substance use disorders, and they screen inadequately for preclinical cases
(32,36,37). Because they neither find patients with less severe addiction nor
follow up those who have had success in treatment, most physicians have
experienced few successes. This latter product of poor linkages biases the
spectrum of medical clinicians’ clinical experience and further discourages
physician involvement. In effect, only patients who do poorly and develop
severe medical and psychosocial consequences are “visible” (38). In such an
environment, it is difficult to convince even well-meaning clinicians that the
diagnosis and management of these disorders are worthwhile; however, training
can help overcome these barriers (39–42). Further, the recent highly visible
opioid overdose epidemic, and complex issues surrounding pain and opioid
prescribing, have served as opportunities to expand addiction education (eg,
http://pcssmat.org/, http://pcss-o.org/,
https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm, https://www.scopeofpain.com/
and https://addiction.surgeongeneral.gov/), including some related to prescribing
that is required in some states for licensure. One example is in Massachusetts. In
2015, the Massachusetts Medical Society developed Opioid Therapy and
Physician Communication Guidelines to assist physicians in developing and
practicing safe opioid prescribing; these guidelines are now incorporated into the
Massachusetts Board of Registration in Medicine’s comprehensive advisory to
physicians on prescribing issues and practices
(http://www.massmed.org/Continuing-Education-and-Events/Online-
CME/Courses/New-Opioid-Prescribing-Guidelines/New-Opioid-Prescribing-
Guidelines-in-Practice/).
Payment and Service Linkage Issues

In the past, payment for addiction treatment and mental health care has been
limited, compared with payments for other medical services (43,44). Although in
recent years, there have been successes in the effort to achieve parity for
healthcare benefits; nonetheless, parity has not yet been fully realized in
practice.
In 1950, the United States passed the Uniform Accident and Sickness Policy
Provision Law (UPPL), which stated that insurers are not liable for any loss
sustained or contracted while the insured is intoxicated or under the influence of
any “narcotics.” Since 2001, numerous organizations including the National
Association of Insurance Commissioners, the American College of Surgeons,
and the American Medical Association (AMA) have supported the repeal of the
UPPL. In 2010, several states took steps to repeal their UPPLs; for example, in
New York, the No Fault Intoxicated Driver Bill (S.B. 7485) requires insurance
companies to compensate healthcare providers for emergency services provided
regardless of whether the injury was the result of driving while intoxicated.
However, as of 2016, some health plans in 24 states still had exclusions that
enable insurers to deny members’ medical coverage for injuries that occur while
intoxicated.
Moreover, many managed behavioral health plans have “carved out”
addiction benefits, separating the financing of care for mental health and
addiction from that for the rest of the patient’s ailments (45–49). Such plans have
reduced the utilization of services for addiction treatment, and the effect they
have had on clinical outcomes, quality of care, integration of care, and physician
attitudes remains unclear. Separate systems have frequently fostered the delivery
of episodic, poorly coordinated care for substance-using patients.
However, in 2008, the House of Representatives passed the MHPAEA of
2007 (HR 1424), which sought to improve health for all Americans by granting
greater access to mental health and addiction treatment and prohibiting health
insurers from placing discriminatory restrictions on treatment. HR 1424 went
beyond the 1996 Mental Health Parity Act, which required equity only for
annual and lifetime limits by requiring equity across the terms of the health plan.
The MHPAEA became effective in January 2010, and, in February 2010, the
Federal Departments of Health and Human Services, Labor, and Treasury issued
regulations to implement the federal parity law, and those regulations became
effective for most health plans on January 2011. The MHPAEA applies only to
group health plans with >50 employees and does not apply to the individual
insurance market or group health plans for companies with ≤50 employees, the
latter of whom are subject to current state mental health parity requirements.
Federal agencies have been tasked with implementing the MHPAEA in the
context of the Affordable Care Act, which mandated inclusion of substance use
treatment among the essential health benefits for all insured Americans (50).
Some current systems of payment often do not cover addiction services
provided by primary care physicians; however, as payment systems evolve, this
will likely change. Financial reimbursements to medical and behavioral health
clinicians generally are taken from separate budgets, and the financial benefits of
averted medical complications occur later. Consequently, the cost of treatment
for an addiction that prevents subsequent hepatitis C infection may be viewed as
a treatment expense, rather than as a savings of future medical care costs.
Another financial disincentive to linked services is the perception that costs of
such care may be limitless. The fear of the cost of appropriate addiction services
persists, despite analyses that document the limited effect even a worst-case
scenario would have on healthcare expenditures (51).
In 2007, the White House Office of National Drug Control Policy announced
new healthcare codes for substance use screening and brief intervention. The
AMA’s Level I Current Procedural terminology codes (99408 and 99409) went
into effect in 2008 and allow healthcare providers to report and be reimbursed
for structured screening and brief intervention. Now that these codes exist, their
success is largely dependent on their uptake and utilization by healthcare
providers. A 2011 study by Harris et al. (52) demonstrated that identifying
substance use disorder treatment and diagnosis and procedure codes has a high
concordance with chart review, which is a positive indication the codes are being
used and are being used appropriately. However, specific billing for these codes
remains infrequent as the service and its reimbursement is often subsumed in
other evaluation and management, and preventive service codes.
Additional means to address reimbursement barriers to integrated care might
include expanding the substance use disorder workforce that can bill Medicaid,
allowing same-day billing of two services, and facilitating easier reimbursement
for medications (35) and reimbursement incentives (53).
Stigma and Concerns about Confidentiality

Stigma remains a fundamental barrier in the treatment of any patient with
alcohol or drug use. In addition to effects on patient behavior, such as limiting
recognition of needs and readiness to accept services, stigma might result in
medical clinicians’ disinclination toward spending time addressing drug and
alcohol issues or a perception of diminished stature of substance use treatment
clinicians. Both outgrowths of stigma impede overall progress.
Medical and mental health clinicians may at times inadequately appreciate
the efficacy of treatment for addiction despite an overwhelmingly supportive
body of research. For example, physicians may not appreciate the comparable
therapeutic value of treatment for alcohol or opioid use disorders relative to
standard treatment for other chronic disorders, such as diabetes mellitus or
asthma (52–55). Interventions to address stigma have been effective in reducing
it. Friedmann et al. found that knowledge, perceptions, and information training
plus an interorganizational strategic planning intervention were an effective
means to change attitudes and intent to refer patients for medication treatment of
addiction in community corrections settings, especially among corrections staff
(42).
Well-meaning concerns about patient confidentiality can be barriers to
effectively linked medical, mental health, and addiction care. Practical
difficulties interfere with obtaining timely two-way written releases of
information. Title 42 of the Code of Federal Regulations (CFR) part 2 (42 CFR
part 2), the Confidentiality of Alcohol and Drug Abuse Patient Records, was
promulgated in 1975 (40 FR 27802) and revised in 1987 (52 FR 21796) to
ensure that a patient receiving treatment for a substance use disorder in a part 2
program is not made more vulnerable by reason of the availability of their
patient record than an individual with a substance use disorder who does not
seek treatment. On February 17, 2017, the 1987 version was replaced with a
revised CFR part 2 renamed the Confidentiality of Substance Use Disorder
Patient Records (82 FR 6052)
(https://www.federalregister.gov/documents/2017/01/18/2017-
00719/confidentiality-of-substance-use-disorder-patient-records). Though the
protection of patient confidentiality is noble, in some cases, it can impede
integrated care. Although intended to protect patients with substance use
disorders, special addiction information protection may inadvertently reinforce
stigma against patients by supporting the misconception that substance use
disorders are different from other health conditions and must be kept private
resulting in increased stigma and further inhibiting the delivery of
comprehensive integrated care (56,57).
The dissemination of electronic health records (EHRs) has resulted in a
major revolution in information sharing across systems. EHRs create the
potential for real-time data-sharing networks, information sharing protocols
among the health sector and treatment organizations, central warehousing of
health information, and cross-organizational data management. Additionally,
incorporation of SBIRT and substance use screening and assessment tools and
data into EHRs may increase the utilization of these tools and standardize their
implementation across settings and clinicians (58). In the United States, projects
such as the Agency for Healthcare Research and Quality’s State and Regional
Demonstration in Health Information Technology Project are working toward
interoperability and sharing of patient data between hospitals, physician offices,
labs, and other healthcare providers. However, regulatory barriers, such as
patient opt-in provisions (where patients must give written permission to have
their data included in a local or regional registry), will need to be addressed to
maximize utility of these systems. Uptake of Internet-based systems in the
addiction treatment sector will need an influx of resources, as occurred in the
healthcare sector (but not in the specialty addiction treatment sector) with the
American Recovery and Reinvestment Act of 2008.
Further expansion of health information technology including patient portals
brings additional opportunities to integrate patients with substance use disorders
and psychiatric disorders into primary care. The integration of addiction
information into electronic medical records will continue to be challenging.
Regulators and clinicians will continue to struggle to balance protections against
discrimination with the need for information sharing among healthcare providers
in integrated systems of care. Such integration of care is encouraged by the
Affordable Care Act, with central involvement of patient-centered medical
homes in treating and managing substance use, with the benefit of electronic
medical records and electronic data exchanges (for more information,
see http://www.ncsl.org/research/health/the-medical-home-model-of-care.aspx).
In summary, the barriers to an integrated system of care for patients with
substance use disorders are manifold. Barriers include issues of professional
responsibility, education among clinicians, financial disincentives, concerns
about confidentiality, and stigma, among others. Though the barriers can appear
to be extensive, they are not insurmountable. Educational barriers might be
addressed with the use of e-learning technology, the development of clear
guidelines, the development of supportive materials (53), role models, and
greater integration of biopsychosocial model into healthcare education. At the
“macro” level, addressing systems linkages would go a long way toward
improving integrated care. Examples of system approaches include
implementation of the following: linkage models of care, payment systems that
encourage linkage, and quality measures that value coordinated care. Parity of
healthcare benefits for mental health, addiction, and medical conditions can help
to reduce stigma and improve care coordination, but impediments to the care of
addiction in primary care settings exist even in states where parity legislation has
been enacted. These impediments include the arbitrary health insurance practice
of discounting or denying primary care reimbursement for visits in which the
clinician indicates a mental health or addiction condition as the primary
diagnosis (59).
Confidentiality issues can be addressed at the system level by having all care
occur under the umbrella of one health system facilitating record availability and
at an individual patient–clinician level by having office systems that prompt
clinicians and staff to obtain patient information releases to allow healthcare
providers to communicate. Recently published and future studies demonstrating
the feasibility and effectiveness of these models should help to convince payers
and practitioners of the need to move in this direction.
The growth of office-based opioid agonist treatment has enhanced
communication between some primary medical care clinicians and opioid
treatment staff members and provides models for the opportunity of integrating
addiction treatment into medical care. At the clinician level, various approaches
can be taken simultaneously to help overcome the barriers to integration.
Physician attitudes, skills, and practices can be changed by active learning
educational programs (39,40). Convincing theoretical and empirically proven
benefits of linked services also will lead clinicians to favor better-integrated care
(60–62).
MODELS OF LINKED SERVICES

Alcohol- and drug-using patients use services in “inefficient” ways (eg,
emergency department [ED] presentations rather than outpatient clinic visits),
and they do not receive care in the continuous, longitudinal, and comprehensive
manner that is often essential for high-quality preventive care and for the
management of any chronic disease (63–66). Two basic models have been
proposed to bring the system of care for patients with substance use disorders
closer to a primary care or chronic disease management (CDM) model (Table
31-2). One model uses a centralized approach in which treatment of addiction,
primary medical care, and mental health services are colocated at a single site. A
second model uses a distributive approach to facilitate effective patient referrals
to services at different sites. This section describes these models of linked
primary medical, mental health, and addiction services and reviews the available
evidence of their success in facilitating the multidisciplinary care of addicted
patients (22,67).
TABLE 31-2 Features of Centralized and Distributive

Integrated Service Models
Centralized Models
Centralized or on-site models bring primary care, mental health, and/or addiction
services together at a single site. This fully integrated, “one-stop-shopping”
model has been best described in primary care medical clinics and in addiction
treatment programs. In addition to overcoming the substantial political,
bureaucratic, attitudinal, and financial barriers that separate addicted persons
from needed services, centralized delivery overcomes the problems of
geographic separation, patient disorganization, and poor motivation that inhibit
patients with addiction from keeping outside appointments (68–71). In a review
by Korthuis et al., the authors looked at 12 representative models of integration
of medication assisted treatment (MAT) into primary care and found that all
models included some degree of four components (pharmacological therapy,
psychosocial services, integration of care, and education and outreach) and that
the ideal model of care for a particular setting depended on local factors
including available expertise, the population, proximity to an addiction center of
excellence, reimbursement policies, and geography (72).
Willenbring and Olson (73) reported favorable results for a model of
integrated medical and alcohol treatment in a specialty clinic, so-called
backward integration for poorly motivated, medically ill individuals with DSM-
IV–defined alcohol dependence. Their model included at least monthly visits,
outreach to patients who missed appointments, clinic notes that cued the primary
care provider (PCP) to monitor alcohol intake at each visit, provider-delivered
brief advice that emphasized reducing the harm from alcohol use and cutting
down rather than strict abstinence, verbal and graphic feedback of improvement
and deterioration in biological markers such as gamma-glutamyl transferase
(GGT) (74), and on-site mental health services as needed (75,76). In a
randomized design, medically ill alcohol-dependent patients in the integrated
clinic were compared with similar patients referred to traditional alcohol
dependence treatment and ambulatory medical care. During 2 years of follow-
up, patients in the integrated clinic had improved alcohol treatment outcomes
(including greater abstinence), improved outpatient visit adherence, and lower
mortality (77). Though this model may prove too elaborate for many primary
care settings, it serves as a starting point for a disease management system for
substance use disorders, perhaps a specialty disease management clinic similar
to those established for asthma, diabetes mellitus, and congestive heart failure.
With further study, this model may prove cost-effective for patients with severe
alcohol use disorder whose disease is not responsive to less intensive measures.
Less resource-intensive intervention models developed for problem drinkers
in primary care also have proved feasible. The cost analysis of project Trial for
Early Alcohol Treatment, a randomized study of physician-delivered brief
interventions, showed modest improvements in self-reported drinking and
estimated that there would be substantial savings for society and health systems
(78). A primary care study from the University of Massachusetts reported that
2.5 hours of primary care clinician training in patient-centered alcohol brief
intervention was feasible (39) and reduced self-reported alcohol consumption
among “problem drinkers” (79). Saitz et al. (80) demonstrated that a systems
intervention (physician prompting with suggested courses of action) can improve
counseling about alcohol and reduce drinking. In another model of addressing
alcohol use disorder in primary care, O’Connor reported the successful treatment
of patients with naltrexone (81); in three randomized trials, outcomes in such a
model have been similar to those achieved in specialty addiction care (82). Other
models have incorporated behavioral health personnel into primary care
practices (83). However, if these efforts are to be generalized to primary care
settings as they exist today, substantial training of clinicians will be required as
physicians often estimate their competence in alcohol-related behavior change
lower than in other health-related behavior change such as smoking cessation,
stress, exercise, and weight management (84).
Recent studies have demonstrated the effectiveness of incorporating
pharmacological treatment for alcohol use disorders in the primary care setting.
Lee et al. described the feasibility of utilizing long-term extended-release
naltrexone plus medical management in alcohol-dependent adults in two public
primary care clinics. The authors found that 62% of participants completed a 12-
week observational study and that during an additional 48-week active extension
phase, 29% continued treatment for a median of 38 weeks total (range, 16-72
weeks). In active extension phase participants, self-reported drinking days were
low compared to 30-day pretreatment baseline (median 0.2 vs. 6.0 drinks per
day; 82% vs. 38% days abstinent; 11% vs. 61% heavy drinking days)
demonstrating that long-term extended-release naltrexone in a primary care
medical management model was feasible and may promote reductions in
drinking and increased abstinence from alcohol (85). Perhaps most convincingly,
Oslin et al. compared a behavioral health specialist working with the primary
care physician to specialty clinic referral in a randomized trial and found that
engagement was higher and heavy drinking lower in those treated in primary
care (86).
Prior to the Drug Addiction Treatment Act of 2000, few US studies had
integrated treatment of illicit drug use disorders into primary care. Though
general practitioners have frequently participated in the management of these
disorders elsewhere in the world, this occurred later in the United States with the
enactment of legislation permitting office-based treatment of opioid use disorder
with Schedule III, IV, or V pharmacological agents approved for the treatment of
DSM-IV–defined opioid dependence by the U.S. Food and Drug Administration
now about a decade and a half ago. Sublingual buprenorphine and a combination
of buprenorphine and naloxone have been used for this purpose in the United
States since 2003. Several studies have found that buprenorphine works as well
as methadone for patients with opioid use disorders of mild to moderate severity.
In a 12-week randomized trial of 46 opioid-dependent patients treated with
buprenorphine, there was higher retention in the primary care setting than in a
drug treatment program (78% vs. 52%; p = 0.06) and lower rates of opioid use
based on urine toxicology (63% vs. 85%; p < 0.01) (73). In addition to achieving
positive treatment outcomes, office-based buprenorphine has been well received
by patients. Furthermore, not only is treatment with buprenorphine effective in
primary care, the benefit of the addition of specialized counseling over
medication management alone has not been demonstrated (87). Barry (88)
surveyed 142 opioid-dependent patients receiving primary care–based
buprenorphine/naloxone. Their mean overall satisfaction with treatment was 4.4
(of 5). Patients were most satisfied with the medication and ancillary services;
and they indicated a strong willingness to refer a substance-abusing friend for
the same treatment. With the development and dissemination of new
pharmacological therapies for alcohol and other substance use disorders, the
impetus for addiction services in the primary care setting will only increase.
Though methadone is an effective treatment for opioid use disorder, its use is
heavily regulated. Few experimental programs have looked at the use of medical
methadone maintenance involving stabilized methadone patients in a medical
setting. In a study by Merrill et al. (89), regulatory exemptions were granted to
establish a methadone medical maintenance program. Of the 30 enrolled stable
methadone patients transferred to a medical office for care, 28 remained after 1
year and only two patients had opioid-positive urine tests. In addition to good
substance use disorder treatment outcomes, previously unmet medical needs
were attended to as demonstrated by an improvement in the medical composite
score of the addiction severity index (p = 0.02), and patient and physician
satisfaction was high with an improved attitude of physicians toward methadone
maintenance (p = 0.007).
Centralizing primary medical care, substance use disorder treatment, and
psychiatric services has also proven an effective way to manage concomitant
medical conditions such as hepatitis C, tuberculosis, and HIV. In 2012, the
Centers for Disease Control and Prevention released a report urging the
integration of prevention services for HIV infection, viral hepatitis, sexually
transmitted diseases, and tuberculosis in persons who use drugs stating that
linkage and integration of these services will improve quality, reduce
duplication, increase access, improve timeliness of service delivery, and increase
effectiveness of efforts to prevent infectious diseases that share common risk
factors, behaviors, and social determinants (90). Addiction treatment physicians
often perform initial hepatitis C management including screening for hepatitis C
virus (HCV) antibodies and recommending hepatitis A and B vaccines.
With new direct-acting agents, patients with HCV can be treated in general
medicine settings (91,92). Evidence suggests that across the range of alcohol
use, patients can achieve >90% SVR regardless of amount of drinking, thus
arguing that withholding this effective treatment from those who drink is not
appropriate (93). Additional studies have also shown that current and former
people who inject drugs (PWID) can be engaged successfully in evaluation and
treatment of HCV infection when these services are collocated with methadone
treatment (94–98). Less is known about tuberculosis management within a
centralized medical care and substance use disorder setting. However, O’Connor
et al. (99) demonstrated that by utilizing an admixture of isoniazid and
methadone, 72% of patients receiving methadone who were eligible for
tuberculosis chemoprophylaxis completed therapy. The delivery of HIV care in
opioid treatment programs has also been shown to improve retention and
increase medication adherence and viral suppression (100).
Centralized models of primary medical and mental health care in addiction
treatment settings may also improve addicted patients’ access to these services
(101). Umbricht-Schneiter et al. (70) found that 92% of patients randomly
assigned to a centralized model in a methadone treatment program received
medical services, compared with only 35% of patients referred to a local clinic.
A trial of veterans found that primary care on-site in an addiction treatment
program increased attendance at primary care (adjusted odds ratio [OR] = 2.20;
95% confidence interval [CI] = 1.53-3.15) and engagement in addiction
treatment at 3 months (adjusted OR = 1.36; 1.00-1.84) but showed no effect on
overall health status or costs (102). Among patients with substance use–related
medical conditions, integrated care models compared to independent care
models have shown significant decreases in hospitalization rates (p = 0.04),
inpatient days (p = 0.05), and emergency room use (p = 0.02) (103). Similarly,
Friedmann et al. (101) found that on-site delivery of primary care to patients
receiving methadone and long-term residential patients reduced subsequent ED
and hospital use. Other work suggests that integration of addiction treatment and
community mental health services reduces relapse and improves social stability
for patients dually diagnosed with addiction and mental illness (75,104,105). A
2013 study by Brooner et al. found that on-site and integrated psychiatric and
substance misuse services in a methadone treatment setting might improve
psychiatric outcomes compared with off-site and nonintegrated substance misuse
and psychiatric care. On-site participants were more likely to initiate psychiatric
care (96.9-79.5%; p < 0.001), remain in treatment longer (195.9 vs. 101.9 days;
p < 0.001), attend more psychiatrist appointments (12.9 vs. 2.7; p < 0.001), and
have greater reductions in Global Severity Index (GSI) scores (4.2 vs. 1.7; p =
0.003) than were off-site participants (106).
The integration of buprenorphine into HIV primary care settings has been
funded by the U.S. Department of Health and Human Services. Through this
program, Lucas et al. compared HIV clinic–based buprenorphine treatment with
referral to an opioid treatment program and found that the HIV clinic–based
group receiving on-site buprenorphine had increased access to opioid agonist
treatment and improved addiction treatment outcomes (107).
In general, patients with nicotine use, at-risk drinking, and low-severity
illicit drug use can be managed in primary care settings without subspecialty
addiction medicine consultation. Conversely, patients with severe substance use
disorders generally should be cared for in collaboration with addiction specialists
and/or treatment counselors (whether integrated in a primary care office or
located elsewhere). However, it is uncertain, except in more severe cases and in
cases where treatment response is not seen, when such specialty care must be
invoked. Recent advances support and encourage a major role for primary care
physicians and office-based psychiatrists in the pharmacological management of
patients with opioid or alcohol use disorder while at the same time recognizing
the need for substantial collaboration and coordination with addiction treatment
providers in some cases. For example, with the availability of office-based
buprenorphine/naloxone, the primary care physician or general psychiatrist can
prescribe medication for opioid use disorder while counseling (which can be
similar to that provided in the medication management of hypertension) is
delivered by the physician, a health behavior expert in the practice, or referral.
Similarly, medications for alcohol use disorder can have efficacy when given
along with low-intensity medication management counseling that addresses
adherence, side effects, and alcohol use (80); such counseling can be done in
medical settings because it is similar to adherence counseling for medications for
other chronic conditions such as hypertension and diabetes mellitus. As with
buprenorphine (87), medications for alcohol use disorder can be as effective
when delivered with medication management counseling as with more
specialized behavioral counseling.
All patients should have primary and preventive health care—again, where
this care is delivered will depend on the system of care. An ideal centralized
model of care can provide addiction, mental health, and medical care at a single
site. Whether specialty addiction medicine or addiction psychiatry services are
delivered at an addiction specialty treatment site or within the primary care
setting, the key is that systems be integrated to deliver the most appropriate and
efficient care.
Chronic Disease Management Model

CDM, also referred to as chronic care management (CCM), is a care delivery
approach based on the chronic care model described by Wagner that links,
integrates, and coordinates primary and specialty care (108,109). It is also
sometimes described as a collaborative care model. The key components are an
informed and motivated patient, a proactive team, and an established delivery
system resulting in maximized CDM and outcomes. Such an approach has been
successfully applied to many chronic diseases but not yet to substance use
disorders. In the AHEAD study, Saitz et al. (110) proposed that the
implementation of CDM focused on substance use disorders should include
attention to (a) systems of care; (b) addressing medical, psychiatric, and social
problems; and (c) addiction-specific treatments. The systems component
addresses the fragmentation of care through on-site longitudinal service delivery,
referral agreements, multidisciplinary teams, coordination of an explicit care
plan, patient reminders, electronic medical records, and collaboration of
addiction, medical, and psychiatric physicians. Medical, psychiatric, and social
components include assessment, management, and coordination of care with
specialty referral. Addiction-specific components include all treatments with
evidence for efficacy such as motivational interviewing, relapse prevention
counseling, ambulatory withdrawal management, and appropriate referral. It has
been hypothesized that strong CDM linkages within and between systems of
care and integrated case management will increase access and receipt of, and
retention in, effective substance use disorders and medical treatment that in turn
will improve utilization and health outcomes. In the AHEAD randomized trial of
CCM for substance use disorders, investigators found few benefits for the group
that received care management versus a control group receiving usual care (111).
However, in a secondary data analysis of the AHEAD study, Kim et al. (112)
demonstrated that high-quality CDM for substance use disorders may improve
addiction outcomes and that chronic care model quality measures may better
reflect effective CDM than measures such as visit frequency. It is possible that
despite the logical and possible effectiveness of the approach, that CDM also
requires the health system at large to improve facilitation of care for patients
with complex chronic conditions.
Additional guidance may be found in implementation science, which studies
the best methods to promote the systematic uptake of clinical research findings
and other evidence-based practices into routine practice (113). LaBelle et al.
studied the Massachusetts Collaborative Care Model in which nurses working
with physicians play a central role in the evaluation and monitoring of
individuals with opioid use disorder treated with buprenorphine and found that
program expansion into 14 community health centers increased the number of
physicians who were waivered to prescribe buprenorphine by 375% within 3
years (114). In a clinician-randomized trial by Upshur et al., the chronic care
model for disease management for alcohol use problems was studied among
women in a health care for the homeless clinic. Women with problem alcohol
use received either usual care or an intervention consisting of a PCP brief
intervention, referral to addiction services, and ongoing support from a care
manager (CM) for 6 months. While baseline differences and small sample size
limit generalizability, both groups significantly reduced their alcohol
consumption, with a small effect size favoring intervention at 3 months;
intervention women also had significantly more frequent participation in
substance use treatment services (115). Studies using implementation indices
(eg, the Behavioral Health Integration in Medical Care [BHIMC] index) to
measure integration capability at baseline and follow-up may help to target
technical assistance and resources (116). Additional studies of how to integrate
substance use interventions in the medical care setting are ongoing (117,118). It
has been difficult to demonstrate benefits of CDM on substance use disorder
outcomes. This difficulty suggests that attention to focused approaches based on
specific diagnoses, patient needs and severity, and implementation details will be
important if benefits are to be achieved.
Distributive Models
In light of the lack of parity in reimbursement for the treatment of substance use
disorders and the absence of unified budgets for medical and behavioral health
services (104), most providers lack resources to provide comprehensive,
centralized services for addicted patients. Moreover, patients (especially those in
long-term recovery) may object to long-term primary care in settings primarily
identified as addiction treatment programs. Therefore, the development and
dissemination of effective decentralized or distributive models is an important
step toward service integration in the current healthcare environment.
Successful referral is the central task of the distributive model. Anecdote and
limited data suggest that simple referral alone cannot integrate the care of
addicted patients in primary care settings. For example, among 1,440 patients
who were in addiction treatment with a primary care physician, 45% reported
that the physician who cared for them was unaware of their addiction (6). Thus,
the substantial interorganizational distance between addiction treatment
programs and mainstream health care presents great barriers to successful
referral. Because people with substance use disorders can have disorganized
lifestyles and poor motivation, contemporary distributive models typically use
case management to facilitate referrals. Community-based case management can
effectively link patients to needed services (119,120).
The hospital setting serves as another point of contact with patients where
linkages can be established between traditional medical care and addiction
treatment. Liebschutz et al. randomized hospitalized individuals using opioids to
a five-day buprenorphine withdrawal management protocol or buprenorphine
induction, intrahospital dose stabilization, and postdischarge transition to opioid
agonist treatment with buprenorphine and found that compared with an inpatient
withdrawal management protocol, initiation of and linkage to buprenorphine
treatment is an effective means for engaging medically hospitalized patients who
are not seeking addiction treatment and reduces illicit opioid use 6 months after
hospitalization (121). In addition to the establishment of linkages between the
inpatient setting and addiction treatment, there is some evidence that linkage
between the ED and addiction treatment services may also be beneficial.
D’Onofrio et al. compared three interventions for DSAM-IV–defined opioid-
dependent patients in the ED: (a) screening and referral to treatment (referral);
(b) screening, brief intervention, and facilitated referral to community-based
treatment services (brief intervention); and (c) screening, brief intervention, ED-
initiated treatment with buprenorphine/naloxone and referral to primary care for
10-week follow-up (buprenorphine) in opioid-dependent patients who were
treated at an urban teaching hospital ED. The study found that among opioid-
dependent patients, ED-initiated buprenorphine treatment versus brief
intervention and referral significantly increased engagement in addiction
treatment, reduced self-reported illicit opioid use, and decreased use of inpatient
addiction treatment services but did not significantly decrease the rates of urine
samples that tested positive for opioids or of HIV risk (122). Nonetheless, while
promising, these studies need replication before widespread adoption.
In addiction treatment programs, distributive arrangements are commonly
used to link patients to medical and mental health services (123,124).
Distributive arrangements range, for example, from an addiction treatment unit
that contracts with a local group practice to provide physical examinations and
routine medical care to its patients to one that makes ad hoc referrals to a local
community mental health center. The advantage of this model is that it makes
use of existing healthcare systems. For example, patients in an inpatient
withdrawal management unit who received a facilitated referral to primary care
in the local community from a multidisciplinary team (physician, nurse, and
social worker) were more likely to link with primary medical care (123). This
model requires no rearrangement of existing healthcare delivery systems;
however, it does require efforts (and therefore costs) to assure that linkage is
facilitated.
Case management or transportation assistance can facilitate these referrals
(125,126). A study of public addiction treatment programs found that contracted
referral with case management increased medical services utilization two- to
threefold over ad hoc referrals (119).
There is also some evidence for the efficacy of a model utilizing a
combination of centralized and distributive approaches. Islam et al. describe a
primary healthcare facility that implemented a hepatitis C treatment assessment
plan that served PWID. Their efforts resulted in successful referrals to a tertiary
liver clinic (71% of those referred attended) utilizing facilitated appointment
scheduling, phone and SMS appointment reminders, confirmation of attendance,
referral outcome communication, and immediate rescheduling of missed
appointments (127). Lastly, another model has emerged to improve access to
addiction treatment. In a model called ECHO (Extension for Community
Healthcare Outcomes), teams of specialists at academic centers provide clinical
expertise for specific cases using videoconferencing, an approach particularly
useful for rural areas (128).
Vulnerable Populations
Integrated models may be most germane and show the most benefit to vulnerable
populations including HIV-infected, homeless, incarcerated individuals, veterans
and active military, and young adults. Integrated models have been found to
promote delivery of HIV-related care, medication adherence, and outpatient
medical services (129,130). An analysis of data gathered from New York State
Medicaid claims found that regular drug use treatment and medical care reduced
hospitalizations by ~25% among HIV-positive and HIV-negative patients with
drug use diagnoses (131). In a recent study investigating patient satisfaction and
experience with buprenorphine/naloxone treatment and integrated care, patients
described being more engaged with both their substance use treatment and HIV
care, including greater ability to manage their own treatment, keep up with
appointments, and adhere to antiretroviral medication regimes (132). Further
research is needed to determine which of these models will be most feasible and
effective and whether they can be applied to other addiction treatments in
addition to buprenorphine.
There is an increasing prevalence of substance use and multiple substance
use among urban homeless persons, who have unique needs that will require
tailored interventions (133). Homeless individuals have high rates of social
instability, comorbidity, and chronic drug use, which make them ideally suited
for systems of integrated care. Alford et al. (134) conducted a retrospective
medical record review of 44 homeless and 41 housed patients enrolled in office-
based opioid treatment over 12 months. They found that homeless patients
receiving buprenorphine/naloxone fared comparably to housed patients.
Treatment failure for the homeless (21%) and housed (22%) did not differ (p =
0.94). Both groups had similar proportions with illicit opioid use (OR, 0.9; 95%
CI, 0.5-1.7 p = 0.8), utilization of counseling (homeless, 46%; housed, 49%; p =
0.95), and participation in mutual help groups (homeless, 25%; housed, 29%; p =
0.96) at 12 months. A key to this approach is a low barrier to entry—without
requirements that would be impossible for homeless adults to meet in order to
receive treatment.
Centralization of addiction services within existing primary care systems
may also play a role in special populations such as incarcerated individuals by
decreasing emergency room visits and hospitalizations and improving care of
substance use disorders and other chronic conditions upon their release.
Substance use is common in incarcerated individuals, with a recent systematic
review finding drug use disorder in male prisoners ranging from 10% to 48%
and in female prisoners from 30% to 60% (135). Despite the high prevalence of
substance use disorders in correctional settings, a survey of the medical directors
of all 50 states and the federal prison system demonstrated that, among
respondents who had jurisdiction over 88% of US prisoners, 48% provided
methadone, predominantly for short-term withdrawal management and pregnant
inmates, and only 8% referred DSM-IV–defined opioid-dependent inmates to
methadone programs upon release (136). Lack of medications for opioid use
disorders in jails and prisons places incarcerated individuals at high risk for
relapse, overdose, and hospitalization following release (137), (138). In a
randomized trial of continuation of methadone versus forced withdrawal among
incarcerated offenders, the former was found to increase treatment engagement
after release and had the potential therefore to reduce risk behaviors, overdose,
and death (139). Boyd et al. showed that within the year following jail release,
the presence of a substance use disorder increases the frequency of ED use,
while being retained in HIV primary care decreases the frequency of ED use
(140). The high prevalence of substance use disorders in incarcerated individuals
and the limited treatment options create a gap in services. Efforts to close that
gap should include improved treatment matching and linkage of services both
during and after incarceration (141,142).
Veterans and active military are another vulnerable population that can
benefit from improved treatment linkages. Fareed et al. reviewed the medical
records of 102 patients who received treatment at the Atlanta VA Medical Center
methadone clinic between 2002 and 2008 to assess an on-site health screening
and brief health counseling intervention to improve the delivery of health
services for chronic medical conditions. They found that illicit opioid and
cocaine use markedly decreased in patients overall, and the effect was more
robust for those successfully “retained” in treatment (p < 0.0001), compared to
those who “dropped out” of treatment (p = 0.05). Additionally, adherence to
primary care appointments was high for “retained” patients (82% and 88%
before and after the on-site intervention, respectively), and hemoglobin A1c
improved by 40% after the on-site intervention as reflected by the decreased
percentage of patients with A1c > 7% from before to after the intervention (90%
vs. 50%, p = 0.05). The authors concluded that the need for and potential benefit
of enhancing the delivery of health promotion services for chronic medical
conditions in patients receiving methadone are evident, and improving
management of hepatitis C, diabetes, hypertension, and other related conditions
in this high-risk, difficult-to-treat, and underserved population may reduce their
morbidity and premature mortality (143).
Young adults (ages 18-24) have the highest rates of substance use disorders
and co-occurring psychiatric disorders. In a study of young adults attending a
psychiatrically integrated residential substance use disorder treatment program,
Bergman et al. found that young adults with both substance use disorders and co-
occurring psychiatric disorders, despite more severe clinical profiles at intake,
had similar improvements in clinical targets (eg, coping skills, abstinence self-
efficacy) and outcomes during the year post discharge when compared with
young adults with substance use disorder only. The authors suggested that for
young adults with co-occurring disorders, residential substance use disorder
treatment programs that integrate evidence-based psychiatric services be
considered (144).
In summary, several effective models of centralized and distributive linkage
in primary care and specialty addiction treatment settings have been developed.
Addiction interventions in medical settings are appropriate for a spectrum of
patients: at-risk drinkers and those with substance use disorders of mild to
moderate severity, medically ill substance-dependent patients who refuse formal
treatment referral, and patients with substance use disorders who receive
rehabilitative counseling elsewhere yet would benefit from addiction-related
pharmacotherapy and management of their medical problems. With adequate
support, primary care physicians also can have a productive role in outpatient
withdrawal management (145). Minimally motivated patients who will accept
only harm reduction interventions can benefit from management in the primary
care setting as well. For patients in formal addiction treatment, linkage to needed
medical and psychological services may improve access to health care, improve
physical and mental health, and reduce relapse. Both centralized and distributive
models show promise for integrating care across these systems. The distributive
model predominates in the United States (146). Though it can be less effective
than the centralized model in linking substance-using patients to needed services
(68,147), its relatively low cost, flexibility, and adaptability (especially to
integration of secondary and tertiary care services) suggest that the distributive
model, with further refinements, is likely to remain the method of coordinated
services in the near future. Although with the advent and increasing adoption of
office-based addiction treatments using pharmacotherapy, the impact of
integrated systems of care within primary care will be of great interest to
patients, doctors, other providers, as well as policy makers and researchers.
PROSPECTS FOR IMPROVED LINKAGE

Despite the enormity of the challenge, momentum is building for a
transformation in the configuration of addiction treatment and healthcare
services. A number of signs suggest that a window of opportunity exists for
innovation. The staggering burden of medical and mental health problems
affecting substance-using patients is now well documented, from HIV, hepatitis
C, and drug overdose to depression, anxiety, and victimization (148–151). The
enormous economic burden that substance use problems place on our society,
through costs related to health care, criminality/incarceration, and loss of
productivity, is increasingly recognized and forces policymakers to consider
alternative approaches to the management and care of this population (152,153).
Moreover, advances in the diagnosis and treatment of substance-related
disorders, including pharmacological and behavioral approaches applicable in
the primary care setting, promise to change the approach to clinical management
of these prevalent disorders. The perspective that the current century is an
opportune time to advance the linkage of substance use treatment with mental
health and medical care was fully endorsed in a report from the IOM,
“Improving the quality of healthcare for mental and substance use conditions:
The quality chasm” series (22). An underlying theme in the book is that only by
addressing substance use and mental health problems can one achieve optimal
benefit for patients engaged in medical care. One of the most important
recommendations of the IOM report pertains to the delivery of coordinated care
among primary care, mental health, and substance use treatment providers. The
basis of this recommendation lays in the Crossing the Quality Chasm “rules”
that endorse “shared knowledge and the free flow of information” and
“cooperation among clinicians.”
Primary care and disease management systems are not achievable if only
adopted by physicians but rather require a multidisciplinary team. Thus, the
reported sense of overburdening of physicians should not preclude the
development of linkage systems but rather influence their development so that
their implementation does not solely rely on physicians’ functions (154). The
ability to treat addictions in less intensive settings will promote cost savings and
cost-effectiveness. Increased attention to the improvement of quality in
healthcare systems also presents opportunities to address linkage to addiction
treatment as a quality issue. Finally, the current era has seen rapid reorganization
of healthcare services and the emergence of accountable care organizations.
Despite the challenges associated with such transitions, they provide
policymakers the opportunity to rethink inadequate systems. These realities can
create a climate of innovation toward the delivery of high-quality,
comprehensive, and coordinated care for patients with substance use disorders.
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CHAPTER 32
Alternative Therapies for Substance Use
Disorders
David Y.W. Lee
CHAPTER OUTLINE
Introduction
Herbal Remedies with AntiAddictive Potential
Transcutaneous Electrical Acupuncture Stimulation as a Noninvasive
Alternative Therapy for Unhealthy Alcohol and Drug Use
Opioid Withdrawal Management with Transcutaneous Electrical
Acupuncture Stimulation
Prevention of Craving and Relapse to Opioid Use
Acupuncture and Unhealthy Alcohol Use
Conclusion
INTRODUCTION
Addiction is a complex process with physiological, behavioral, psychological,
and social components, so treatment is usually multifaceted. There are two
fundamental approaches: prevention of the onset of compulsive use and
prevention of relapse and the craving that leads to relapse. In the past, much
medical attention has been directed at the symptoms of acute abstinence
(withdrawal management), and these symptoms can be treated with available
therapies and medications. However, relapse, which may be precipitated by
withdrawal and/or craving even after prolonged abstinence, poses the most
serious therapeutic challenge. In view of the current opioid epidemic in the
United States, the complexity of substance use disorder (SUD), and the limited
number of effective treatments, it is conceivable that certain selected alternative
pharmacotherapies may have important clinical significance. This chapter
reviews traditional herbal medicines and therapies for the prevention of drug and
alcohol relapse.
HERBAL REMEDIES WITH

ANTIADDICTIVE POTENTIAL
Herbal remedies, which usually consist of a complex mixture of herbs, have
been used in China for thousands of years to treat human disease. Poppy has
been known in China for 12 centuries and for its medicinal use for 9 centuries.
Opiates, alkaloids derived from poppy, effectively activate the endogenous
opioid system in the body. This activation produces many cardiovascular,
endocrine, immune, and neuropsychological effects including euphoria,
analgesia, and addiction. It has been clear that the effects of opioids are mediated
through interaction with specific opioid receptors. Moreover, studies of the
binding of various related opioid compounds in the brain indicate the existence
of at least three opioid receptor types such as μ, κ, and δ (with multiple subtypes)
(1). Since the rewarding effects of opioids are mediated primarily through action
at μ-opioid receptors, interference with actions at these receptors presents a
rational strategy for developing medications for the treatment of opioid use
disorder (2,3). Specifically, medications that block activation of μ-opioid
receptors (eg, naltrexone) might reduce drug-seeking behavior (1,3,4).
It was not until the middle of the 19th century that smoking opium for
recreational purposes was practiced throughout China. The quantity of opium
imported into China rose from 5,000 chests in 1820-16,000 in 1830, 20,000 in
1838, and 70,000 in 1858. After more than a century of aggressive opium
distribution by European powers, with half the Chinese population (nearly that
of the US population today) addicted, China finally determined to give up
opium, which ultimately led to the “Opium Wars.” During this period, Chinese
herbal remedies were developed for treating addiction or relieving the
withdrawal syndrome.
The Chinese remedies developed during the Opium Wars era were
combinations of more than a dozen herbs; thus, a mixture of herbs may well
represent a multitargeted approach, perhaps acting on opioid receptors that
would have the benefits of improved overall efficacy with reduced toxicity.
However, it is necessary to isolate and characterize the bioactive compounds as
well as elucidate the mechanism of actions for further development of safe and
complementary natural medications for SUDs. Few original remedies have been
investigated scientifically. One, YGT (NPI-025), consists of five herbs (Qiang
Huo, Gou Teng, Chun Xiong, Fu Zi, and Yan Hu Suo) most frequently used for
SUD treatment in China. Yang et al. (5) observed YGT effects among 300
individuals with “drug addiction” over a 10-year period and reported that NPI-
025 significantly was associated with reduced withdrawal symptoms (−48%)
compared to addicted individuals without treatment. Follow-up visits of many
“cured” patients 1-3 years after treatment suggested that the use of NPI-025 may
have been associated with overcoming craving for drugs.
After the cloning of the mouse κ-opioid receptor (6,7), μ, δ, and κ receptors
of several species were cloned (for reviews, see (8,9)). These cloned opioid
receptors provide excellent tools for pharmacological screening of traditional
remedies for SUDs. For instance, YGT (NPI-025), used clinically in Hong Kong
(5,10), was subjected to bioactivity-guided fractionation and showed that the
alkaloids, such as L-tetrahydropalmatine (L-THP) isolated from one of the
component (Yuan Hu), show potent opioid receptor–binding activities (11).
These studies provide important evidence for further development of such
natural products.
Corydalis yanhusuo
Corydalis yanhusuo (Fig. 32-1) is one of the five Chinese medicinal plants in
NPI-025. Chemical fractionation resulted in the isolation and characterization of
l-tetrahydropalmatine (l-THP) (Fig. 32-2) as one of the bioactive components.
Optical resolution or chemical synthesis resulted in pure l-THP, which is the
active compound with significant binding activities to D1 and D5 dopamine
receptors.
Figure 32-1 Corydalis yanhusuo.
Figure 32-2 Structure of dopamine, isocorypalmine, and l-

tetrahydropalmatine (THP).
Dopamine Receptors and Pharmacological Actions of l-

THP
Despite extensive research for new approaches, there is currently no effective
pharmacotherapy for cocaine or methamphetamine addiction (12–14). Some
effects of l-THP on cocaine and methamphetamine self-administration have been
demonstrated (15,16), suggesting potential, but not yet proven, clinical utility.
Cocaine binds differentially to the dopamine, serotonin, and norepinephrine
transporter proteins and directly prevents the reuptake of dopamine, serotonin,
and norepinephrine into presynaptic neurons (17–19). Inhibition of reuptake
subsequently elevates the synaptic concentrations of each of these
neurotransmitters, thus potentially reducing craving for cocaine and
methamphetamine but also possibly causing reward, reinforcement, and
addiction on their own.
Two types of dopamine receptors, D1 class and D2 class, mediate dopamine
neurotransmission. The D1 class includes both D1 and D5 receptors, while the
D2 class includes D2, D3, and D4 receptors (20). There is a high-density
distribution of D1 and D2 receptors in the striatum, which is relevant to the
pharmacology of cocaine. Recent preclinical studies suggest that drugs that are
selective for D1 or D2 receptors may reduce some aspects of cocaine self-
stimulation (21,22) or ethanol self-administration (23). Though both selective
D1 and D2 receptor agonists can reduce cocaine self-administration, these agents
can also mimic the discriminative stimulus produced by cocaine and stimulate
locomotor activity (24–26); therefore, there is a risk that these drugs may also
have potential for unhealthy use and addiction and would not be useful in
practice for cocaine treatment.
Though selective D1 receptor agonists or D2 receptor antagonists might
modulate cocaine-induced behavior (27), they have side effects that prevent
them from becoming useful therapeutic agents. Indeed, preliminary clinical
studies have not provided promising results (28,29). Because of the limited
success of these selective compounds, interest has turned to medications that
may have dual actions. In particular, a medication that stimulates D1 receptors
and blocks D2 receptors may have the right profile to become a promising
treatment for cocaine or drug use. A recent study of one such compound, an
ergoline derivative (LEK-8829) with D1 agonistic and D2 antagonist
characteristics, attenuated reinstatement of cocaine seeking induced by cocaine-
priming injections and diminished cocaine intake in cocaine self-administration
sessions (30). Thus, it has a better profile than selective D1 receptor agonists
alone for inhibiting cocaine self-administration. Furthermore, LEK-8829
reduced cocaine reinstatement behavior but did not induce reinstatement of
cocaine. The combined results suggest that the strategy of using compounds with
dual D1 receptor agonist/D2 receptor antagonist properties to treat SUDs may be
worth pursuing.
Similar to LEK-8829, plant-derived l-THP has both D1 receptor agonist and
D2 receptor antagonist actions. Its effects on cocaine and methamphetamine
addiction are suggested (15,16). One mechanism is that l-THP appears to
suppress the expression of stimulant-induced conditioned place preference
(CPP). l-THP could also block the discrimination behavior for methamphetamine
and the reestablishment after its extinction. Interestingly, it has been reported
that l-THP suppresses the craving/relapse for cocaine in addiction. Thus, these
findings suggest that l-THP may have potential as a novel natural medication for
inhibiting the craving/relapse of the psychostimulants addiction including
cocaine and methamphetamine.
In summary, l-THP and l-isocorypalmine, a demethylated analog of l-THP,
are two interesting compounds isolated from C. yanhusuo. In vitro binding study
showed that both l-THP and l-isocorypalmine have affinity toward D1 and D5
receptors. In the functional assay, l-isocorypalmine is more potent than l-THP as
D1 and D5 partial agonists. It is interesting to note that the partial skeleton of
both l-THP and isocorypalmine resembles the dopamine molecule (see Fig. 32-
2) with different number of methoxy group attached. These bioactive compounds
derived from fractionation and in vitro screening may provide a better
understanding of the mechanism of action of NPI-025 as a whole. One study as
shown in Table 32-1 revealed that l-isocorypalmine is the metabolite of l-THP
and has strong affinity to D1 and D5 receptors.
TABLE 32-1 Corydalis Yanhusuo and Dopamine

Receptor Activity
Ki values (nM) of L-THP, L-ICP, L-SPD, and L-SLR binding to 5 cloned human DA receptors stably
expressed in HEK293 cells. Radioligand: [3H]SCH23390 (1 nM) for D1/D5 and [3H]N-methylspiperone
(0.3 nM) for D2/D3/D4. Each value represents mean ± S.E.M. of three experiments performed in
duplicate.
Uncaria rhynchophylla
Uncaria rhynchophylla (Fig. 32-3) is an important traditional Chinese medicine
used in the treatment of pain, infantile convulsions, headaches, dizziness,
hypertension, and rheumatoid arthritis. Uncaria rhynchophylla is another
ingredient in NPI-025 (5). In order to clarify the mechanism of action, 12
compounds have been isolated by solvent extraction, followed by silica gel
fractionation and Toyopearl HW-40, MCI gel column chromatography. Two
major alkaloids, rhynchophylline and isorhynchophylline (Fig. 32-4), have been
identified as potential/unproven antiaddictive compounds with moderate binding
activity for dopamine receptors [3H]DIP rMOR and [3H]DIP mDOR. The
clinical significance of these findings is not clear.
Figure 32-3 Uncaria rhynchophylla.
Figure 32-4 Structures of rhynchophylline and

isorhynchophylline.
Reduction of Alcohol Drinking by the Extract of

Pueraria Lobata
Isoflavone compounds naturally occurring in the root of the kudzu plant
(Pueraria lobata) have been used historically to treat alcohol-related problems
(31). Early work by Overstreet et al. (32,33) showed that the herbal formula
NPI-028, which contains P. lobata, reduced acute alcohol consumption in two
strains of alcohol-preferring rats when administered parenterally (0.25-1 g/kg
i.p.) or orally (1 and 1.5 g/kg) without affecting water intake. Daily treatment
with 1 g/kg i.p. for 5 days also was effective, as was 0.18-0.75 g/kg i.p. in
African vervet monkeys. Several studies have systematically explored the ability
of three major isoflavones of kudzu root—daidzin, daidzein, and puerarin—to
reduce alcohol consumption in animals and humans. The effects of the
isoflavones singly on alcohol consumption also have been studied. Keung and
Vallee (34) showed that daidzin reduced consumption by 50% in Syrian golden
hamsters. Heyman et al. (35) showed a dose-related decrease in alcohol-
reinforced lever pressing by daidzin in rats. Puerarin was effective in two
studies: Lin et al. (36,37) showed a 40% reduction of intake in female alcohol-
preferring rats given 100 mg/kg/d for 7 days mixed in food and a 65% reduction
at 300 mg/kg/d. In the same study, daidzin and daidzein 100 mg/kg/d reduced
consumption to 75% and 50%. Benlhabib et al. (38) showed a 50% suppression
of intake in rats by puerarin 50 mg/kg. In humans, Lukas et al. (39) studied the
effects of a kudzu root extract that contained 25% isoflavones (19% puerarin,
4% daidzin, 2% daidzein) in heavy drinkers. Three grams of the extract (750 mg
total isoflavones) was administered for 1 week before a 1.5-hour afternoon
drinking session. In comparison to drinking following the placebo week, there
was a significant reduction in beer consumption in addition to several significant
changes in drinking topography, including an increase in the number of sips
taken to finish a beer and an increase in the latency to open subsequent beers. In
a second study, where the same extract was administered for 4 weeks in an
outpatient setting, Penetar et al. (40) found a significant reduction in intake
during weeks 2 through 4. Building on these encouraging results, we repeated
the in-laboratory afternoon drinking session paradigm with the single isoflavone
puerarin and found that participants consumed on average 3.5 (±0.6) beers after
placebo and 2.4 (±0.4) after puerarin. None of the puerarin subjects drank five or
six beers, while three placebo subjects drank five, and one drank all six (41).
These studies demonstrate that puerarin may reduce alcohol drinking in humans.
However, the mechanism of action of puerarin remains to be elucidated, and the
implications outside of laboratory settings remain to be confirmed.
TRANSCUTANEOUS ELECTRICAL
ACUPUNCTURE STIMULATION AS A
NONINVASIVE ALTERNATIVE
THERAPY FOR UNHEALTHY ALCOHOL
AND DRUG USE
In a serendipitous observation in 1972, Dr. H. L. Wen in Hong Kong noted that
electroacupuncture relieved a patient’s withdrawal from opium (42). Dr. Wen
and Dr. Cheung at the Kwong Wah Hospital (42) subsequently reported that, in a
study of 40 individuals addicted to heroin and/or opium, acupuncture combined
with electrical stimulation was effective in relieving withdrawal. This method
was later adopted in many clinical settings in Western countries, including the
Lincoln Hospital in New York. However, the body acupuncture points originally
used by Wen and Cheung on the arm and hand were gradually omitted, with only
auricular acupuncture being used (43), and electrical stimulation also was
omitted, leaving only needles staying in situ. Whether these two omissions will
affect therapeutic efficacy deserves further investigation.
The discovery of morphine-like substances (endorphins) in the mammalian
brain (44) had a great impact on acupuncture research. It was soon made clear
that acupuncture-induced analgesia (manual needling) can be blocked by the
narcotic antagonist naloxone, suggesting the involvement of endogenous opioid
substances (45). In animal experiments, manual acupuncture or acupuncture
combined with electrical stimulation (electroacupuncture, or EA) was shown to
accelerate the production and release of endorphins that can interact with
different kinds of opioid receptors to ease pain (46). It was further clarified that
endorphins are, in fact, a group of neuropeptides possessing different
characteristics. Among these neuropeptides, β-endorphin and enkephalin are
primarily agonists at μ- and δ-opioid receptors, whereas dynorphin is an agonist
at κ receptors (47). Interestingly, electrical stimulation of different frequencies
can induce the release of different kinds of endorphins. For example, low-
frequency (2-4 Hz) EA accelerates the release of enkephalins to interact with μ
and δ receptors, whereas high-frequency (100 Hz) EA accelerates the release of
dynorphin to interact with κ receptors (48). These findings strengthen the
scientific basis of this ancient healing art and point the way to its use in areas
beyond pain control.
It is natural to hypothesize that if acupuncture can release endogenous
opioids in the brain to ease pain, it might relieve withdrawal symptoms. In fact,
the first observation made by Dr. Wen in 1972 was that he attempted to use
acupuncture for reducing surgical pain and incidentally found that it ameliorated
the opioid withdrawal syndrome. This hypothesis was tested in morphine-
addicted rats. Withdrawal signs were significantly reduced by high-frequency
(100 Hz) EA administered on the hind limb acupoints St 36 and Sp 6 (49). This
effect was much greater than that induced by low-frequency (2 Hz) stimulation.
On the basis of these results, EA was applied to individuals addicted to heroin
and obtained very promising results. However, it was inconvenient for patients
to go to the clinic for treatment several times a day. As a result, they missed
sessions, thus affecting the therapeutic outcome. One possible solution was to
have patients treat themselves by using acupoint stimulation without a needle but
still under the control of a physician. To overcome this problem, Han et al.
developed a constant current electrical stimulator: Han’s Acupoint Nerve
Stimulator (HANS).
Experiments in the rat using HANS showed that electrical stimulation
applied at the surface of the skin over acupoints can produce an analgesic effect
similar to that produced by EA (50). Satisfactory results were obtained using this
transcutaneous electrical acupoint stimulation (TEAS) by HANS for the
treatment of heroin withdrawal syndrome in humans (51). Later, the method was
shown to suppress CPP, an animal model of craving for morphine in rats (52).
Subsequent human studies revealed that this form of stimulation could indeed
suppress craving in patients with opioid use disorders.
OPIOID WITHDRAWAL MANAGEMENT

WITH TRANSCUTANEOUS
ELECTRICAL ACUPUNCTURE
STIMULATION
Animal Studies
Systematic studies have revealed that the mechanism of acupuncture analgesia is
attributed mainly to the increased release of endogenous opioid peptides in the
central nervous system (CNS) (46). A rational extrapolation would be that the
activation of the endogenous opioid system by acupuncture should ease opioid
withdrawal symptoms.
Transauricular electrostimulation was reported to suppress the naloxone-
induced morphine withdrawal syndrome in mice (53) and rats (54). Auriacombe
et al. (55) demonstrated that transcutaneous electro nerve stimulation with an
intermittent high-frequency current effectively attenuated signs in the rat after
abrupt cessation of morphine; the mechanism remains obscure. Based on the
findings that low-frequency EA (2 Hz) accelerated the release of β-endorphin
and enkephalin in the CNS, whereas high-frequency EA (100 Hz) accelerated the
release of dynorphin (48,56) in the spinal cord, the effect of EA was tested in
naloxone-precipitated morphine withdrawal in the rat. Because the effect of 2 Hz
EA is to accelerate the release of the morphine-like opioid peptides enkephalin
and endorphin, it was predicted that 2 Hz would be more effective than 100 Hz
in replacing morphine and ameliorating the abstinence syndrome. However, 2 Hz
was only marginally effective in reducing two of five withdrawal signs, whereas
100 Hz suppressed all five signs (49).
Human Studies
To observe the effect of TEAS on the withdrawal syndrome in patients with
opioid use disorders, the method was applied for 30 minutes once a day for 10
days in an addiction treatment center (51). In addition to a standard
questionnaire, two objective parameters were measured—heart rate and body
weight.
Single Treatment
To observe the immediate effect on heart rate, the two pairs of output leads were
placed on four acupoints in the upper extremities: one pair at Hegu (LI4) on the
dorsum of the hand and on the palmar aspect of the hand opposite to LI4 Laogon
(P-8), to complete the circuit, and the other pair at Neiguan (PC6) on the palmar
side of the forearm 2 inches above the palmar groove between the two tendons
and Waiguan (TE5) on the opposite side of PC6. A dense-and-disperse (DD)
mode of stimulation was administered, with 2 Hz alternating automatically with
100 Hz, each lasting 3 seconds. This mode was shown to release four of the
opioid peptides in the CNS (48), thus producing maximal therapeutic effect. The
control group received the same placement of electrodes, which were
disconnected from the circuitry. The average heart rate of the abstinent
individuals was 109 beats per minute before treatment. DD stimulation for 30
minutes reduced the heart rate significantly, as shown in Figure 32-5. Reduction
occurred within the first 5-10 minutes, continued for 20 minutes, and plateaued
at 90 per minute in the last 10 minutes. The aftereffect remained for 20 minutes,
after which the heart rate began to return to the original level (57).
Figure 32-5 Effects of 2/100 Hz electric stimulation (HANS)

on the heart rate of individuals with opioid use disorder
during episodes of withdrawal. *,** represent p < 0.05 and p
< 0.01, respectively, compared with control groups.
(Reprinted from Han JS, Trachtenberg AI, Lowinson JH.
Acupuncture. In: Lowinson JH, et al, eds. Substance Abuse:
A Comprehensive Textbook. Philadelphia: Lippincott
Williams & Wilkins, 2004:743-782, with permission.)
Multiple Treatments
To observe the cumulative effect of multiple daily treatments with TEAS, 117
individuals with opioid use disorder were divided randomly into four groups.
Three groups received TEAS of 2 Hz (constant frequency), 100 Hz (constant
frequency), or 2/100 Hz (2 Hz alternating with 100 Hz, DD mode). The control
group received mock stimulation, where the skin electrodes were placed on the
points and connected to the stimulator with blinking signals but with the electric
circuitry disconnected. The treatment was applied for 30 minutes a day over 10
consecutive days. Heart rate was measured with an electrocardiogram before and
immediately after the TEAS stimulation. Figure 32-6 shows the results. In the 2-
Hz group, for example, on the first day of observation, the heart rate averaged
110, which dropped to 90 immediately after the TEAS treatment (p < 0.01). On
the second day, the heart rate averaged 102 and then fell to 91 after TEAS (p <
0.01). This trend continued for days 3 and 4. On day 5, there was no significant
difference before and after the treatment (91 vs. 89), suggesting that the rate had
returned to “normal” (51). In the three TEAS groups, 100 Hz produced a slightly
better result than 2 Hz. In the 2/100 Hz group, the after-TEAS rate reached an
even lower level (72 beats). Also, the 2/100 Hz returned to “normal” in day 4, 1
day earlier than the fixed frequency groups (day 5). In the control group (n = 30)
receiving mock TEAS, the rate did not come down to 100 until the eighth day of
treatment. These results suggest that repeated daily EA treatment is effective in
reducing tachycardia in individuals with opioid used disorder, with an order of
DD >100 Hz >2 Hz (see Fig. 32-5). Body weight was also affected. The age of
the patients ranged from 17 to 35, and their average weight was only 49-51 kg.
In the control group receiving mock TEAS, weight declined by 1 kg at the end of
the first week, probably owing to the presence of withdrawal distress. In the
TEAS groups, weight had increased significantly after 4 days of treatment and
continued to increase thereafter. By day 10, the TEAS groups weighed 5 kg
more than the control group. This 10% increase was apparently due to reduced
withdrawal symptoms and increased food and water intake. Though the DD
mode was significantly better than the fixed frequency mode in reducing
tachycardia, weight change did not differ among the three TEAS groups,
suggesting that the mechanisms modulating heart rate and body weight may not
be identical (51).
Figure 32-6 Changes of heart rate before and after treatment
by TEAS administered every day: A normalization of the
heart rate was obtained by day 4 (C) or day 5 (A and B). ** p
< 0.01 compared with after treatment (ANOVA). (Reprinted
from Han JS, Trachtenberg AI, Lowinson JH. Acupuncture.
In: Lowinson JH, et al, eds. Substance Abuse: A
Comprehensive Textbook. Philadelphia: Lippincott Williams
& Wilkins, 2004:743-782, with permission.)
In clinical practice, opioid withdrawal symptoms could be reduced but not

abolished by the TEAS treatment, especially in those cases with a history of
heroin use for more than 5 years. To obtain a quantitative estimate of the efficacy
of TEAS (58), (a) TEAS was applied on the acupoints Hegu/Laogong,
Neiguan/Waiguan, and Xingjian/Sanyinjiao. Buprenorphine (BPN, i.m.) was
used as a supplement to TEAS when the patient experienced a specified degree
of withdrawal distress and was given immediately upon request. The purpose of
this arrangement was to maintain a comfortable withdrawal management
procedure without any withdrawal syndrome. In this study, 28 individuals with
opioid use disorder were randomly divided into BPN only and TEAS + BPN
groups. Figure 32-7A shows the results. The group receiving TEAS required
only 8% of the BPN required by the group not receiving TEAS. This can be
taken as a quantitative estimate of the effect of TEAS for opioid withdrawal
management. The sharp difference observed between the mild and short-lasting
therapeutic effect on day 1 (see Fig. 32-5) and the large effect by day 14 (Fig.
32-7) suggests an accumulation of efficacy produced by repetitive treatments. A
similar reduction occurred in another group of individuals with opioid used
disorder, those with a methadone reduction protocol for the control group and “a
TEAS (2/100 Hz) plus methadone” experimental group with a reduction of 75%
methadone use for the TEAS + methadone group (59). This finding needs further
evaluation prior order to being considered a standard addiction treatment.
Figure 32-7 Influence of 2/100 Hz electric simulation
(HANS) on the requirement of BPN (A) or methadone (B)
for heroin withdrawal management. ** p < 0.01 compared
with the corresponding control group. (Reprinted from Han
JS, Trachtenberg AI, Lowinson JH. Acupuncture. In:
Lowinson JH, et al, eds. Substance Abuse: A Comprehensive
Textbook. Philadelphia: Lippincott Williams & Wilkins,
2004:743-782, with permission.)
PREVENTION OF CRAVING AND
RELAPSE TO OPIOID USE
Drug addiction is a chronic and recurrent condition. A high rate of relapse after
prolonged drug-free periods characterizes the behavior of experienced users of
heroin and other drugs. Once addiction is established, craving can last for a long
period of time. The protracted withdrawal syndrome and the craving for drugs
often drive the patient to relapse. Recently, electrical acupuncture has been
shown to reduce craving and postpone or prevent relapse (52).
Animal Studies
Several animal procedures have been proposed to model craving (60).
Conditioned Place Preference has been frequently used (61). The drug
(unconditioned stimulus) is given in one chamber of a two- or three-chamber
apparatus, thereby becoming associated with the environmental stimuli unique to
that chamber (color, floor texture, etc.). After repeated pairings, the rat will
spend more time in the chamber associated with drug. The ratio between the
times spent in drug-associated and vehicle-associated areas is assumed to reflect
the degree of craving. CPP has been regarded as a relatively pure measure of
psychic dependence in that the preference for the drug-associated chamber can
be demonstrated when the rat is in the undrugged condition and free of
withdrawal symptoms. Experiments were done to determine whether
acupuncture could suppress the expression of CPP.
Wang et al. (52) were among the first to explore the effect of EA on
morphine CPP in the rat. They found that 2 Hz and 2/100 Hz significantly
suppressed CPP but that 100 Hz did not (Fig. 32-8A). Since the effect of EA can
be reversed by a dose of the opioid receptor antagonist naloxone (Fig. 32-8B)
that is sufficient to block μ and δ but not κ receptors, it was concluded that the
effect of EA is mediated by endogenously released μ- and δ-opioid agonists,
most likely endorphins and enkephalins, to ease craving for exogenous opioid (in
this case, morphine). Another issue deserving attention is that the effect of EA
was demonstrable 12 hours after application. Acupuncture-induced analgesia
usually disappears within 1 hour. Thus, EA might sensitize endogenous opioid
circuits to produce a continuous release of opioid peptides, resulting in a long-
lasting effect.
Figure 32-8 A: Effects of electroacupuncture on 4 mg/kg
morphine-induced CPP (n = 11-12). ** p < 0.01, compared
with four control groups as well as the group treated with
100-Hz stimulation. B: Naloxone blockade of the inhibitory
effect of electroacupuncture on morphine-induced CPP (n =
9-0). ** p < 0.01, compared with the needling control group.
## p < 0.01, compared with their corresponding naloxone-
treated group. (Reprinted from Han JS, Trachtenberg AI,
Lowinson JH. Acupuncture. In: Lowinson JH, et al, eds.
Substance Abuse: A Comprehensive Textbook. Philadelphia:
Lippincott Williams & Wilkins, 2004:743-782, with
permission.)
In the everyday life of those with drug addiction, craving and relapse can be
triggered by stress or by a very small dose of opioid. This phenomenon can be
reproduced in the rat CPP model. Wang et al. (52) reported that morphine-
induced CPP disappeared after a 9-day extinction period and was reinstated by
foot shock stress or by a small dose of morphine or amphetamine. Reinstated
CPP could be reversed by 2 Hz or 2/100 Hz EA, an effect easily reversed and by
naloxone (62). However, the mechanisms of EA suppression of morphine CPP
may involve different neural pathways.
Human Study of Cravings

To obtain a quantitative estimate of suppression of craving in response to
acupuncture or related techniques, a visual analogue scale (VAS) in individuals
with opioid use disorder at least 1 month after withdrawal management was
used. The scale for the VASE is 100 mm long: 0 is equal to no craving and 100 is
equal to the most severe craving imaginable. One hundred seventeen subjects
were assigned randomly into four groups. Three groups received TEAS at 2 Hz,
100 Hz, or 2/100 Hz. Self-adhesive skin electrodes were placed on four
acupoints: Hegu and Laogong (palmar side of the Hegu point) on the left (or
right) hand to complete the circuit and Neiguan and Weiguan on the right (or
left) arm to complete the circuit. The intensity was increased from threshold on
the first day to two or three times threshold on the following days. The mock
TEAS control group was processed like the other groups except that the intensity
was minimal (at threshold stimulation for 3 minutes, followed by 1 mA
thereafter). The results, shown in Figure 32-9, indicate a slow decline of the VAS
in the mock TEAS group and a parallel slow decline in 100 Hz group, in contrast
with a dramatic decline in the 2 Hz and 2/100 Hz groups. In summary, the results
in humans coincided with the results in rats—that low frequency is more
effective than high frequency in reducing craving for opioids (62).
Figure 32-9 Effects of HANS on craving scores in

individuals with opioid use disorder (n = 29-30 in each
group). HANS of 2 Hz and 2/100 Hz accelerated the decay of
craving scores during the 10-day treatment period. (Reprinted
from Han JS, Trachtenberg AI, Lowinson JH. Acupuncture.
In: Lowinson JH, et al, eds. Substance Abuse: A
Comprehensive Textbook. Philadelphia: Lippincott Williams
& Wilkins, 2004:743-782, with permission.)
On the basis of the experimental effects of TEAS described earlier, the subjects
were encouraged to take with them a portable TEAS unit when they were
discharged from the withdrawal management center. The purpose was to
ameliorate the protracted withdrawal syndrome and to suppress the craving
induced by environmental cues. At least one 30-minute session before going to
bed was recommended to facilitate sleep, as was use whenever they encountered
a cue. It was found that the anticraving effect usually appears within 20 minutes.
ACUPUNCTURE AND UNHEALTHY

ALCOHOL USE
Acupuncture was considered promising for the treatment of alcohol addiction in
the 1980s. The orthodox ear points suggested by National Institute on Drug
Abuse were used, with points 3-5 mm apart as a nonspecific control. Two papers
provided positive results (63,64). However, these results could not be replicated
in the United States (65) or Sweden (66). A recent randomized placebo-
controlled clinical trial of auricular acupuncture (67) (N = 503) was unique in
that, aside from the “specific” ear acupuncture group, “nonspecific” ear
acupuncture group, and conventional treatment group, there was a symptom-
based acupuncture group for which the acupuncturists were not constrained to
the four ear points stipulated for the other acupuncture groups, and the point
prescription could be changed from day to day according to the patients’
discomfort. Six treatments per week were given for as long as 3 weeks to
maximize the effect. All four groups showed significant improvement, with few
differences associated with treatment assignment and no treatment difference on
alcohol use measures, though 49% of subjects reported that acupuncture reduced
their desire for alcohol. The authors concluded that ear acupuncture did not
make a significant contribution over and above that achieved by conventional
treatment in the reduction of alcohol use.
There are abundant published data to show that endogenous opioid peptides
mediate the euphoric effect of alcohol (68) and that the opioid antagonist
naltrexone can assist cognitive behavioral therapy for patients with alcohol use
disorder (69). Therefore, modulation of the endogenous opioid system is one of
the approaches for the treatment of alcohol use disorder. Yoshimoto et al. (70)
reported that rats subjected to repeated restriction stress consumed more alcohol
than controls. EA at hind limb points Zusanli (ST-36) significantly reduced
alcohol seeking, but EA at the lumbar point Shenshu (BL-23) did not. EA at ST-
36 was accompanied by a higher dopamine level in the striatum than was EA at
BL-23. These findings provide intriguing information for understanding alcohol-
drinking behavior and for treating those with alcohol use disorder.
CONCLUSION
In view of the current opioid epidemic in the United States, and the lack of
effective remediation, there is an urgent need to develop safe and effective
“Alternative Therapies” for treating SUDs. Traditional Chinese medicines have
been used for treatment of human disease for more than 2,000 years. It is
estimated that roughly one-half of current pharmaceuticals originally were
procured from plants (71). Examples include foxglove leaf (digitalis),
belladonna tops (atropine), poppy herb (morphine), white willow tree bark
(salicin), and cinchona bark (quinine). Modern drugs developed from plant
products include warfarin from coumarin anticoagulants found in sweet clover
silage, ergotamine from ergot alkaloids of a fungus that infects rye grass,
antineoplastic vincristine from the vinca alkaloid fractions of the rosy
periwinkle, the anticancer drug paclitaxel from pacific yew tree, and antimalarial
artemisinin from Qingdao (72). It is therefore reasonable that medication
development for unhealthy drug and alcohol use should seek active isolates from
traditional herbal remedies.
That said, many believe that a combination of medicinal plants with
synergistic effects is a better approach. Though it is difficult to prove the
synergism of multicomponent herbal remedies, the concept of a multitargeted
approach is familiar to Western medicine as the basis of chemotherapy for most
cancers and highly active retroviral therapy for HIV disease. It is also
conceivable that a multitargeted approach would improve the overall efficacy
and reduce toxicity. This is because human diseases including addiction are
highly complex and the efficacy of a single chemical entity targeting one disease
site or receptor is often limited. On the other hand, as Chung et al. (73) reported
multicomponent natural products with good in vitro binding activities used
successfully to treat psychotic illness in Korean traditional medicine.
Although acupuncture and related acupoint therapies are most commonly
recognized for analgesic effect, their medical applications extend beyond pain
treatment. Though alternative therapies may provide new treatments for existing
drug treatments, rigorous studies to evaluate both the risks and the benefits of
such treatments are needed. Biological investigations that couple in vitro and in
vivo pharmacological models to characterize the mechanism of action and the
possibility of synergistic effects of components are crucial to further the
development of successful complementary and alternative therapies for SUDs
and related conditions.
ACKNOWLEDGMENTS
The work was supported by a grant funded by NCCIH/NIAAA for Center for
Excellence for Research on Complementary and Alternative Medicine (P01-
AT002038) and (R01AT-006899).
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CHAPTER 33
Harm Reduction, Overdose Prevention,
and Addiction Medicine
Alexander Y. Walley, Sharon Stancliff, and India Perez-
Urbano
CHAPTER OUTLINE
Harm Reduction Definition and Principles
History of Harm Reduction
The Integration of Harm Reduction and Addiction Treatment
Interventions that Reduce the Harms of Substance Use
Threat to Harm Reduction: Potential for “Corporate Capture” by Substance
Industries
Conclusion
HARM REDUCTION DEFINITION AND

PRINCIPLES
Harm reduction is a person-centered, public health approach that seeks to reduce
the harms of substance use to individuals and communities (1,2). Harm
reduction seeks to address the multiple needs of persons with addiction via
practical and evidence-based interventions. Abstinence from substances is one
way to reduce harm, but improved health and functioning of the individual is the
main goal or primary outcome. The approach is person-centered because it
expects care providers to “meet people where they are at” and work with people
who use substances as fully enfranchised collaborators in their efforts to make
their lives healthier.
Harm reduction recognizes the strengths and challenges of individuals who
use substances and acknowledges that reducing substance consumption may not
be feasible, desired, nor the singular way to minimize the harms of substance
use. Fundamentally, harm reduction approaches are built for, and by, individuals
who use substances, with an emphasis on their human rights and
destigmatization. Harm reduction interventions increase engagement with, and
access to, healthcare resources by people who use substances. Efforts are also
taken to assist individuals in accessing and navigating social services and
institutions to ensure basic needs, such as food and housing. Harm reduction
interventions can and should be integrated into the continuum of substance use
prevention and treatment, because they seek to reduce the harms associated with
substance use that may occur before, after, and even during treatment.
Harm reduction includes multiple pragmatic strategies and policies that can
be delivered across a diversity of settings, all of which share the common goal of
improving health and functioning. Table 33-1 includes examples of tangible
harm reduction strategies, many of which will be discussed throughout this
chapter. Many of the adverse health consequences of substance use are not due
directly to the substance itself, but rather to other factors that can be ameliorated
—for example, the transmission of blood-borne infections from sharing injection
equipment. Thus, harm reduction emphasizes the measurement of health, social,
and economic outcomes, over the measurement of substance consumption.
Table 33-1 Harm Reduction Strategies and Mechanisms

of Reducing Harm
HISTORY OF HARM REDUCTION

The evolution of what is now termed “harm reduction” may be traced back to the
establishment of the first syringe–needle access program (SNAP) in Amsterdam.
In 1984, a group of individuals who used drugs called the Junky Union
(Junkiebund), in collaboration with public health officials, developed a SNAP to
prevent the spread of Hepatitis B. SNAPs were widely adopted across Europe
and Australia to reduce the spread of HIV and have been credited in averting an
HIV epidemic (3). In the United Kingdom, the Mersey Harm Reduction Model
responded to the threat of HIV via a collaboration of health educators and
methadone treatment providers who included syringe–needle distribution among
the services (4). The first legally sanctioned SNAP in the United States was
established in Tacoma, Washington, in 1988; however, expansion was hindered
in the United States by laws that banned the use of federal funds for the
provision of syringes and research of these programs (5). Yet despite these
barriers, SNAPs evolved into multiservice organizations serving people who use
substances. Inspired by these programs and the harm reduction approach, other
interventions have been innovated including take-home naloxone rescue kits for
overdose prevention, supervised drug consumption venues, heroin treatment,
pre- and postexposure HIV prophylaxis, Housing First, managed alcohol
programs, and drug checking.
THE INTEGRATION OF HARM

REDUCTION AND ADDICTION
TREATMENT
People who use substances, but who are not willing or able to stop using, are
unlikely to seek out or learn about addiction treatment options. In addition, many
people committed to abstinence may hesitate to engage with harm reduction
programs because they do not want to acknowledge the possibility of relapse and
how to reduce the risks of using. However, integrating harm reduction and
addiction treatment offers benefits to both of these groups (6). People who are
initially not interested in discontinuing their use often develop ambivalence
about continuing their use and then determination to reduce or stop their use.
Thus, an opportunity to engage such a person in addiction treatment emerges
from engagement built on harm reduction. By facilitating access to treatment
through harm reduction programs, high-risk people can initiate treatment earlier
and more conveniently. People with severe substance use disorders, even when
they are committed to abstinence, relapse (7). Relapse includes use despite the
intention not to use a substance, which is one of the eleven DSM-5 criteria for a
substance use disorder (8). Thus, relapse is a definitional expectation for people
with substance use disorders. Treatment programs should work to optimize the
safety of their patients who relapse by incorporating harm reduction strategies,
even if the program has an abstinence focus. Collaboration between, and
integration of, harm reduction and addiction treatment programs can be
complimentary. As an example, Box 33-1 shows an integrated list of treatment
and harm reduction strategies for people who use drugs who are hospitalized (9).
Integration has the potential to enhance the accessibility of effective treatment
and harm reduction interventions to the broad continuum of people who use
substances.
BOX 33-1
CHECKLIST TO OPTIMIZE HEALTH AND
SAFETY IN PEOPLE WHO INJECT DRUGS (10)
High-quality, person-centered harm reduction programs share several principles
with addiction treatment programs and can foster collaboration (10). These
principles include culturally competent, nonjudgmental care, which respects
individual dignity, addresses the socioeconomic and physical consequences of
substance use; incorporates outreach strategies to engage and motivate people
who use substances, and offers specific services that reduce the harms of
substance use for those who continue to use substances. Care providers should
not stigmatize the return to use after abstinence as a failure. Additionally, they
should not restrict access to medical, psychiatric, or addiction treatment due to
the receipt of medication treatment (eg, medical and residential addiction
treatment settings should be open to people treated with methadone). Finally,
they should recognize that collaboration between service programs makes the
continuum of care stronger.
One example of the integration of harm reduction and addiction treatment
includes the incorporation of overdose education and naloxone distribution
(OEND) into the orientation of patients initiating methadone or buprenorphine
treatment, as well as patients undergoing residential medically managed
withdrawal (ie, inpatient withdrawal management) (11). Although decreased
opioid use, including abstinence, is one goal of both opioid agonist therapy and
withdrawal management programs, fatal overdose risk is increased among
people with opioid use disorders (OUDs) treated with methadone in the first 2
weeks of care and among patients leaving (voluntarily or involuntarily) from
opioid agonist therapy and medically managed withdrawal programs. Embedded
OEND addresses the risks of relapse and overdose among people engaging in
addiction treatment by training them on how to keep themselves safer if they
relapse and how to respond to other people’s overdoses.
INTERVENTIONS THAT REDUCE THE

HARMS OF SUBSTANCE USE
Practice Ready Interventions
Overdose Risk Education and Naloxone Rescue Kits to
Prevent Overdose
Unintentional overdose, primarily related to opioids, is a major cause of death in
North America, Europe, Asia, and Australia. The rate of unintentional drug-
poisoning deaths has more than doubled between 1999 and 2012; meanwhile, the
rate of unintentional deaths involving opioid-analgesics more than tripled
between the same time period (12). In addition, 2013 marked the beginning of
unprecedented rates of opioid-related overdose deaths involving illicitly
manufactured fentanyl in the United States, a synthetic opioid that is 50-100
times stronger than morphine (13,14).
Naloxone is an opioid antagonist that reverses the effects of opioid overdose
by displacing opioid agonists (ie, heroin, fentanyl, and oxycodone) from opioid
receptors. Naloxone has minimal to no adverse effects and is standard overdose
treatment used by emergency medical personnel. Distribution of naloxone rescue
“kits”—which typically contain two doses of naloxone and instructions—
alongside overdose reversal and prevention education, has become integral to
community harm reduction programs. Laypersons with potential of being
bystanders to an overdose (ie, people who use drugs, their friends and family,
recently released jail and prison inmates) are a primary target of these programs
as they may fear of calling 911 because of illegal activities or delays in arrival in
rural areas. Because most overdoses evolve over minutes and occur in homes or
residences removed from medical care, community programs train laypersons to
respond to an overdose. Overdose responder training often includes how to
recognize signs of overdose, seek help, rescue breathe and/or provide chest
compressions, administer naloxone, and stay with the person who is overdosing.
Studies have found no evidence of compensatory drug use behavior among
individuals who use heroin after being trained in overdose response and given a
take-home naloxone rescue kit (15).
Overdose prevention programs have been established in many venues,
including syringe access programs, HIV prevention outreach programs,
methadone maintenance clinics, inpatient withdrawal management programs,
emergency department settings, and community meetings (11). To incentivize
individuals to seek medical attention for an overdose, or after naloxone
administration, “Good Samaritan” laws have been introduced in 37 US states
and the District of Columbia to provide legal protection to both the individual
who administered naloxone and the individual who overdosed (16). Good
Samaritan laws grant immunity from arrest or prosecution if in possession of
drug paraphernalia or certain amounts of controlled substances.
In the United States, educating people who use opioids about overdose
prevention and response and equipping them with take-home naloxone rescue
kits started at the Chicago Recovery Alliance in the 1990s (17). Between 1996
and 2014, naloxone programs in the United States provided naloxone training
and rescue kits to 152 283 laypersons and reported 26 463 overdose rescues (18).
Naloxone is also becoming increasingly available at retail pharmacies across the
United States: between late-2013 and mid-2015, naloxone distribution from
retail pharmacies increased by 1170%. Between 2013 and 2016, the Veterans
Health Administration initiated an aggressive campaign to implement OEND
that resulted in over 39 000 patients receiving naloxone rescue kits (19). In many
states, it is available in pharmacies without a patient-specific prescription so that
individuals can access it without visiting a primary care provider. Studies of
naloxone programs have demonstrated feasibility, increased knowledge and
skills, and reduction in fatal overdoses after initiation of community naloxone
rescue programs. In an interrupted-time series analysis of overdose education
and nasal naloxone implementation in Massachusetts, compared to communities
with no naloxone distribution, overdose deaths rates were 47% lower among
communities with high naloxone distribution and 27% lower among those with
low naloxone distribution (20). Another study on coprescribing naloxone to
patients being prescribed opioids, or otherwise at risk of overdose, found a 63%
reduction in opioid-related emergency department visits compared to those not
receiving a prescription (21). The distribution of naloxone rescue kits has also
been found to be cost-effective with estimated incremental cost per quality-
adjusted life-years gained ranging from $438 to $14 000 in a conservative model
(22). Since 2010 in the United States, many police, fire, and emergency
medicine first responders have been carrying and using naloxone, becoming
enthusiastic advocates for widening access to life-saving antagonists.
BOX 33-2
OVERDOSE PREVENTION ONLINE
RESOURCES
Access to Clean Injection Equipment to Reduce HIV,
HCV, and Injection Risk
The first SNAPs were established in the 1980s as an HIV prevention effort in
response to the HIV epidemic among people who inject drugs (PWID). In 2015,
there were 288 SNAPs operating in the United States. Reductions in HIV and
hepatitis C incidence have been shown in several countries where access to new
injecting equipment has been implemented on a large scale (23). A study of 81
cities with HIV seroprevalence data found that cities with SNAPs had a 5.8%
decrease in HIV prevalence per year, whereas cities without SNAPs had 5.9%
increase in HIV prevalence per year (3). In communities where they have been
implemented, SNAPs have reduced HIV incidence by reducing the sharing and
reuse of hypodermic needles. Typically, SNAPs provide not only syringe–needle
access, but also HIV, viral hepatitis, tuberculosis screening, viral hepatitis
vaccination, and on-site referral to substance disorder treatment—to people who
are often otherwise disconnected from medical services. Thus, secondary
benefits have included increased enrollment in substance use disorder treatment
(24,25), increased retention in HIV treatment among PWID, and reduced needle
stick injuries among first responders (26).
SNAPs are typically charged with not only distributing new, sterile needle–
syringes and other injecting equipment but also collecting and disposing of used
needle–syringes and equipment. Some programs operate as “exchanges” where
the number of syringe–needles that are distributed is limited by the number of
syringe–needles that a client brings into the program (27). While the intention of
an exchange requirement is to maximize syringe–needle collection, it limits the
access to new sterile syringe–needles to more stable PWID. Whereas less stable,
less engaged PWID are more likely to be infected and transmit HIV and hepatitis
C. More liberal distribution of injecting equipment has been associated with
safer injection practices and lower HIV incidence compared to more
conservative exchange schemes (28). Thus, peer-delivered syringe–needle
exchange and peer outreach have become explicit elements to many SNAPs.
In many places, syringe–needles are available for purchase in pharmacies
without a prescription (29,30). Because pharmacies are broadly distributed
across communities, pharmacy access to safer injection equipment has the
potential to dramatically increase access. In many countries and communities
where pharmacy access has been pursued and supported as an HIV and hepatitis
C prevention policy, pharmacies have successfully distributed syringe–needles to
PWID. Barriers have also been recognized including pharmacy staff attitudes,
mandated training, and requirements to show identification.
Syringe–needle prescription is a feasible option in communities where
pharmacies require a prescription to distribute syringe–needles. This approach
was implemented successfully in Providence, Rhode Island, in 1999 and
demonstrated feasibility, acceptability, and enhanced communication between
PWID and healthcare providers (31). Prescribers offered syringe–needle
prescriptions as part of general medical care, typically prescribing 100 syringes
at a time. This is complimented by access to a portable disposal container and
discussions on safer injection techniques, how to recognize infections, and safe
disposal of used equipment. A national survey of a representative sample of US
physicians with a 20% response rate found that most respondents were unaware
of the laws in their state around syringe access. Almost half of the responding
prescribers reported they would consider prescribing syringes to prevent
transmission of infections and 3.4% reported that they had prescribed to PWID
for this purpose (32).
BOX 33-3
DISCUSSING SAFER INJECTION WITH
PEOPLE WHO INJECT DRUGS
Despite the evidence, SNAPs have been politically controversial in the United
States due to concerns that they would encourage injection drug use. A ban on
federal funding was initiated in 1988 and continued until it was lifted in 2009;
however, the ban was reinstated in 2011 and then partially lifted in early 2016.
Specifically, the ban on using funds for the purchase of injection equipment
remains, but federal funds may be used for other components of SNAPs, based
on evidence of demonstrated need due to an increase in HIV or hepatitis C
infections. Of note, after an outbreak of HIV infection among people using
injection prescription opioids in Scott County, Indiana, was described in 2015
(33), the state government lifted restrictions and implemented a SNAP through
the public health department, along with increasing access to HIV and addiction
treatment, resulting in controlling new HIV infections.
Clean injection equipment can also be distributed via public syringe-
dispensing machines (SDMs) 24 hours a day, 7 days per week, without the fixed
overhead and staffing costs of SNAPs and without the requirement of walking
into a pharmacy. SDMs have been shown to attract PWID who would otherwise
not go to SNAPs or pharmacies, people who are younger, people who more
recently started injecting, and people with no contact with addiction service
providers. SDMs have been introduced in more than one hundred cities in
Europe, Australia, and New Zealand (34), but not in the United States.
Pre- and Post-HIV Exposure Prophylaxis Medication to

Reduce the HIV Infection
HIV transmission risk can be reduced by taking anti-HIV medication within 24
hours before an unsafe exposure (Preexposure prophylaxis [PrEP]) or within 72
hours after an unsafe exposure (Post-exposure prophylaxis [PEP]). People who
use alcohol and drugs are at risk of transmission of HIV through high-risk sexual
practices and the sharing of injection equipment. High sexual risk includes
having an HIV-positive sexual partner, recent bacterial sexually transmitted
infections (STIs), multiple sexual partners, inconsistent or no condom use, or
commercial sex work. A randomized trial of PrEP among PWID in Thailand
reported a 49% reduction in overall HIV infection risk and a 74% reduction in
HIV risk among those who had the PrEP medication detectable in their blood
(35). Since 2014, the Centers for Disease Control and Prevention (CDC) has
recommended that PrEP be considered for any adult who does not have HIV
infection and who injected drugs within the past 6 months, additionally, those
who have shared injection equipment, enrolled in addiction treatment, or was at
increased risk for sexual transmission (36). Cost-effectiveness modeling has
demonstrated a role for PrEP for PWIDs, along with opioid agonist treatment
and anti-retroviral treatment, in controlling HIV transmission in communities
with HIV epidemics driven by injection use (37). The recommendations for PrEP
include documentation of negative HIV test before initiating PrEP and no acute
HIV symptoms, normal renal function, and no active hepatitis B infection. At 3-
month follow-up intervals, patients taking PrEP should receive an HIV test,
medication adherence counseling, behavioral risk reduction support, side effect
assessment, STI symptom assessment counseling, as well as, lab testing every 6
months for renal function and bacterial STIs.
PEP is indicated for anyone with a high-risk HIV exposure including sexual
assault, unprotected sex, and needle-sharing incidents. PEP involves an
assessment of the risk of the exposure, baseline testing, and prescription of a
three medication regime to be continued for 28 days. Treatment should be
initiated as soon as possible, preferably within 2 hours of exposure, and is no
longer indicated 72 hours after the exposure. PEP can be initiated and followed
in most medical settings; however, the urgency of initiation may necessitate
referral to an emergency department or urgent care. Patients treated with PEP
due to sexual- or injection-related exposure should be subsequently offered PrEP.
Guidelines for PEP and PrEP are available and there is a national hotline for
immediate consultation (38).
Medications to Prevent Injection and Overdose Risks

Treatment of substance use disorders with medications is harm reduction when it
results in reduced complications of substance use. The best evidence for
addiction medication as harm reduction exists for methadone and buprenorphine
treatment for OUDs. Studies have shown that participation in opioid agonist
treatment reduces injection frequency, HIV transmission, overdose (39), and
criminal activity (40)—even among those who continue to use and inject opioids
and other substances (41).
A harm reduction-oriented approach to opioid pharmacotherapy prioritizes
the reduction of risk behaviors associated with morbidity and mortality over
abstinence and strict adherence to a treatment plan. This approach is supported
by the American Society of Addiction Medicine’s guidelines on the use of
medications in the treatment of addiction involving opioids, which recommend
that “The use of marijuana, stimulants, or other addictive drugs should not be a
reason to suspend OUD treatment (42).” The guidelines acknowledge that
concurrent use is associated with poorer outcomes and recommend that the
overall harms and benefits of continuing treatment be weighed in the midst
concurrent use of other substances.
The Drug Addiction Treatment Act of 2000 has allowed the treatment of
OUD in primary care settings. However, the majority of people with OUD are
still not in treatment; innovative models are needed. France allowed for
widespread prescribing of buprenorphine with little regulation. While this policy
has not been problem-free, it has been associated with a dramatic decrease in
overdose fatalities (43). Buprenorphine treatment can be initiated successfully in
inpatient hospitals (44), emergency departments (45), at SNAPs (46), and in
correctional settings (47). Continuing methadone for incarcerated patients
dramatically improves treatment retention upon release (48).
In Europe, Canada, and Australia, other opioids have been used successfully
for opioid treatment to reduce the risks of injecting illicit opioids. There have
been several trials using slow-release morphine (49), heroin (50), and
hydromorphone (51) for patients who have not done well with methadone, which
have shown positive outcomes.
Alcohol: Targeted Use of Opioid Antagonists

Daily use of two opioid antagonists, naltrexone and nalmefene, has been shown
in randomized controlled trials to reduce the number of drinks per day among
people with daily alcohol consumption. The effectiveness of these medications,
as well as acamprosate and disulfiram, has been limited by poor adherence in
many real-world populations. The strategy of targeted or as-needed use, meaning
taking the medication at times when a person is more likely to drink alcohol, has
been examined in several studies of both medications among people with
problem drinking and alcohol use disorders. Relative to daily use, targeted use
has the potential to reduce episodes of alcohol intoxication and the consequences
that follow, while also reducing the risks of side effects of daily medication use
(eg, hepatotoxicity) (52). One study demonstrated greater reductions in alcohol
use from a targeted naltrexone strategy than a daily naltrexone strategy (53).
Although the effect sizes were small, three randomized trials of nalmefene in
Europe have demonstrated improvement in multiple alcohol-related outcomes
over placebo. Targeted nalmefene is approved for the treatment of people with
alcohol use disorders in Europe. Prescribing the medication, without an
abstinence requirement, so that a patient and her or his support network can
decide which days to take the medication and which days to go without is a
patient-centered approach that tries to minimize the inconvenience of taking a
medication daily and is consistent with a harm reduction approach.
Wider Venue Interventions

Supervised Drug Consumption Venues to Reduce
Infection Risk and Overdose
Supervised injection facilities (SIFs), or drug consumption venues, are facilities
where people may go to consume drugs obtained elsewhere under trained
supervision in a hygienic environment, with appropriate equipment, without fear
of arrest. A primary goal of SIFs is to improve the health status of the target
population while also serving as a response to the problem of public injection
(ie, injection of drugs in parks, empty lots, public restrooms) (54,55). The first
SIF opened in Switzerland in 1986. Today, there are more than 100 legally
sanctions sites in at least eight countries; yet, there are none in the United States.
SIFs are similar to other harm reduction interventions in that they are designed
to reduce the risk of disease transmission and other infections; intervene in
evolving overdoses and provide a point of entry into other services. These
facilities target and serve marginalized populations with high rates of housing
insecurity and with HIV and/or HCV.
SIFs are strongly associated with reductions in overdose fatalities in the
vicinity of the facility, with no reported overdose deaths within the facilities
(56). They have not been associated with increases in drug use or drug crimes
(57), but rather cessation of drug injection, increased addiction treatment uptake,
and reduced time to entry into addiction treatment (58). They reduce public
disorder, including public injection and public syringe disposal (59). They have
also been found to reduce risk behaviors for blood-borne infections such as
reusing and sharing injection equipment, while increasing access to drug
treatment and timely access to health care (60). A number of modeling studies
have found that SIFs are likely to reduce HIV and HCV infections and would be
cost-effective and potentially cost-saving (61). Related innovative programs that
seek to create safer venues for people who use injection drugs, but do not offer
fully supervised injection, include monitored spaces for people who are
oversedated from polysubstance use and monitored washrooms at agencies
serving PWID in recognition of the reality that they may be used to inject (62).
Housing First to Reduce Barriers to Housing Among

People Who Use Substances
In many communities in the United States, housing assistance is only accessible
to people on the condition that they commit to sobriety and engage in addiction
treatment. For people with substance use disorders, these contingencies result in
coupling entrenched substance use with entrenched homelessness. There is little
chance for people who use substances as their primary method for coping with
their poverty and homelessness to quit substances and engage in addiction
treatment before being eligible for housing. Housing First programs target
people who are homeless and have behaviors that have traditionally limited their
access to housing (63). These programs seek to reduce health harms and costs by
removing ongoing substance use as a barrier to providing stable housing.
Typically, housing is combined with enhanced support services that both reduce
the harms of ongoing substance use and increase the likelihood of engaging in
treatment. A 2015 meta-analysis of Housing First programs found that shelter
and emergency department costs have been reduced, though overall costs may be
increased (64).
Managed Alcohol Programs

People with severe alcohol use disorder who are actively drinking and homeless
are commonly restricted from housing due to ongoing alcohol use. Housing First
programs are designed to remove this barrier to housing. Managed alcohol
programs further attempt to reduce the harms of daily heavy alcohol use among
people who are homeless by providing alcohol of known quality in order to
stabilize alcohol use with the goals of improving health and well-being, reducing
acute care hospitalizations, recurrent withdrawal management services, and
reduce hazardous alcohol use patterns, including severe intoxication and more
dangerous nonbeverage alcohol, such as methanol and isopropyl alcohol.
Longitudinal observational evaluations of managed alcohol programs have
reported fewer emergency department visits, fewer police contacts, reduced
alcohol consumption within the program over time (65), less nonbeverage
alcohol use, reductions in tests of liver inflammation (66), and improved
perception of quality of life and housing stability (67). Peer-reviewed, published
descriptions and evaluations of managed alcohol programs have come from only
Canada at this point. Randomized controlled trials have not been conducted, but
are warranted, as current evaluations are promising.
Designated Driving
In the United States, the legal blood alcohol concentration limit is <80 mg/dL
(0.08%), but drinking alcohol worsens driving performance at any level in a
dose-dependent fashion. A systematic review of two types of interventions to
address alcohol-impaired driving found little evidence of effectiveness. The first
intervention type was a population-level information campaign that had one
study conducted with a prepost design that showed a 13% increase in
designation of a driver who was not impaired, but no change in self-reported
alcohol-impaired driving or riding with an alcohol-impaired driver. The second
intervention type was the use of incentives at drinking venues to encourage
designated driving. Among seven studies, the number of designated drivers per
venue per night increased by a mean 0.9 (68). More research and innovation is
warranted to determine how best to implement designated driving as a harm
reduction measure.
Drug Testing at Dance Parties to Reduce the Risk of

Ingestion of Contaminants
In response to a burgeoning “rave” and “techno” culture, a number of harm
reduction initiatives emerged to introduce “drug checking” services as a means
to warn partygoers of harmful or unexpected substances. Programs conduct on-
site chemical analyses at dance parties and raves to inform individuals of the
contents of their drug supply. Some programs, such as Dance Safe in the United
States, sell test kits online, allowing individuals to perform their own tests at
home. Programs in The Netherlands, Austria, France, Spain, Belgium, Germany,
and Switzerland have spearheaded pill-testing initiatives across the European
Union, some of which are part of national drug policy (69). Pill-testing has also
served as an important first point of contact between organizations and
individuals they have yet to reach, allowing further engagement in harm
reduction messages and information dissemination (eg, safe sex, designated
driving, drug consumption safety). Additional efforts are often taken to
encourage a “healthy settings approach” by modifying nightlife venues to
improve ventilation, arrange “chill-out” spots, and have first aid teams on site
(70).
Substances commonly used at dance parties and raves such as MDMA
(ecstasy), cocaine, ketamine, lysergic acid diethylamide (LSD), gamma-
hydroxybutyrate (GHB), and flunitrazepam (Rophynol) each pose their own
unique health risks. It is important that consumers are aware of the toxicity,
implications, and contents of their drugs, as a means to estimate level of risk
exposure. For example, test kits can identify the presence of levamisole (a
medication used for veterinary anthelmintic therapy), a common adulterant in
cocaine that has lead to a number of health complications, including necrotic
skin lesions, neutropenia, fatigue, malaise, arthralgias, and even death (71). In
addition, MDMA has been shown to be associated with long-term neurological
impairments and sudden death from rhabdomyolysis, hyperpyrexia, and organ
failure (72). Thus, along with providing chemical analyses, harm reduction
programs will promote hydration and distribute drinking water to ameliorate the
effects associated with loss of body temperature regulation (71). Additionally,
programs will often pass out condoms and informative messages around HIV,
hepatitis C, and other STIs. In the midst of the emergence of illicitly made
fentanyl in North America, harm reduction programs in British Columbia
checked urine samples of participants and found that among 29% of samples
positive for fentanyl, of which, 73% of participants did not report any known
fentanyl use (73).
Within a dynamic and unpredictable drug market, drug checking has
contributed to a multifaceted approach to monitoring and regulating drug market
trends. In The Netherlands, harm reduction programs often serve as a warning
system for participants and will disseminate educational materials (eg, flyers and
media publications) to alert of concerning substances in drug supply (74). The
Trans European Drug Information (TEDI) Project compiled the results of drug
checking efforts from Spain, The Netherlands, Austria, Belgium, Switzerland
and Portugal between 2008 and 2013 and concluded that such chemical analyses
have utility in creating global representations of changing drug market trends
(75).
THREAT TO HARM REDUCTION:

POTENTIAL FOR “CORPORATE
CAPTURE” BY SUBSTANCE
INDUSTRIES
Harm reduction rationale may be subject to “corporate capture” by industries
profiting from the commercial sale of addictive substances. Alcohol industry
marketing has incorporated harm reduction messages, such as responsible
drinking and encouraging designated drivers as alternatives to evidence-based
alcohol policies that have reduced harms (76), such as increasing prices,
restricting availability, and limiting promotion and advertising. Similarly,
postlegalization marketing of marijuana may be driven by large profit-focused
businesses that will market to adolescents to create brand loyalty and physical
dependence, as has been done with alcohol and nicotine (77). While the
decriminalization and legalization of substances reduce the harms of
stigmatizing people who use substances, the commercialization of addictive
substances may threaten the public health gains of harm reduction and its
evidence base.
CONCLUSION
Harm reduction, as an approach to improve the lives of people who use
substances, emerged in the midst of widespread stigmatization and
criminalization of substance use. Several specific harm reduction interventions
that were developed by and for people who use substances have been proven
effective and lie at the core of the public health strategy to address the
complications from substance use. Comprehensive approaches to substance use
and its complications have evolved to incorporate harm reduction, bringing harm
reduction into the mainstream and improving the reach of prevention and
treatment efforts to reach many high-risk individuals. Effective harm reduction
efforts will require ongoing innovation and adaptation in response to the
evolving impact of substances and their complications on public health.
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CHAPTER 34
Quality Improvement for Addiction
Treatment
James H. Ford II, Kim A. Hoffman, Kimberly Johnson,
and Javier Ponce Terashima
CHAPTER OUTLINE
Introduction
Framework for Change
Defining and Measuring Quality Treatment and Outcomes
Accreditation for Treatment Programs
Building System Capacity to Deliver Effective Treatments
Ensuring Primary Care Providers Can Identify, Treat or Refer, and Monitor
Substance Use Disorder
International Efforts: The International Center for Credentialing and
Education of Addiction Professionals
Conclusions
INTRODUCTION
Outcomes from addiction treatment services compare favorably with treatments
for other chronic conditions such as hypertension, diabetes, and asthma (1).
However, addiction traditionally has been treated under an acute care model
where treatment is short term, and postacute support occurs within self-help
groups. A consequence of the discrepancies between the treatment of addiction
and other chronic illnesses is a persistent expectation that patients with
diagnosed substance use disorders (SUDs) remain without substance use after
their treatment ends. For most other chronic health conditions, the expectation is
for long-term symptom management rather than symptom elimination. A
contemporary understanding of addiction as a treatable health condition includes
a recognition that withdrawal of treatment or related supports may promote a
reemergence of symptoms; continuing care by a healthcare provider as well as
active self-management and recovery supports is essential for sustaining positive
outcomes associated with treatment (2,3). Improvement in the quality of
addiction treatment lags behind that of general health care (4) though, as this
chapter will discuss, advancements have been made in recent years.
Efforts to improve the quality of addiction treatment and enhance
effectiveness generally fall into four categories:
1. Defining and measuring quality and treatment outcomes

2. Accrediting and licensing programs and treatment settings that deliver
treatment
3. Building capacity for efficient and effective treatment delivery
4. Ensuring primary care providers can identify, treat or refer, and monitor
SUD
This chapter covers each of these categories. It reviews efforts to define

appropriate outcomes and current trends in accrediting and licensing and efforts
to increase the focus on quality improvement in addiction treatment.
FRAMEWORK FOR CHANGE

National Academy of Medicine Reports
The National Academy of Medicine (NAM, formerly known as Institute of
Medicine [IOM]) within the National Academy of Sciences advises federal
policy makers about health concerns and public health policy issues. In a series
of reports, the IOM identified needs for better health care and outlined strategies
to improve the quality of health care in America. To Err is Human: Building a
Safer Health System (5) found that medical error was a major source of
morbidity and mortality in the US healthcare system and challenged healthcare
systems to track and eliminate error through implementation of performance
standards that emphasize patient safety. Crossing the Quality Chasm: A New
Health System for the 21st Century (6) was the follow-up report. It provided
guidance on redesigning systems of health care to better address chronic care,
make greater use of information and technology, coordinate care, incorporate
process and outcome measures into systems of care, and continually improve the
effectiveness of service providers. Six dimensions of quality were specified: care
should be safe, effective, patient centered, timely, efficient, and equitable (Table
34-1). A third report, Improving the Quality of Health Care for Mental Health
and Substance Use Conditions (4), asserts that the Crossing the Quality Chasm
framework can be extended to treatments for SUDs and other mental health
disorders. The report notes that proven science-based treatments are not used
routinely, services are often fragmented, and substandard care leads to greater
expense and suffering. In addition to the human costs associated with this
treatment gap, there are implications for employers and the workforce, for the
nation’s economy, as well as for the education, welfare, and justice systems. The
report, sponsored by the Substance Abuse and Mental Health Services
Administration (SAMHSA), explicitly recommends that SUD and mental health
treatment systems emphasize the six dimensions of quality of care and that these
public agencies and other payers promote the development of process and
outcome measures that track quality of care (4). Since this report, significant
efforts have been taken to improve measurement and quality although much
work is yet to be done.
TABLE 34-1 Summary of NAM Dimensions of Care
In its most recent report, Psychosocial Interventions for Mental and Substance
Use Disorders (7), the NAM provides a framework “to support policy, research,
and implementation strategies that promote the use of evidence-based
psychosocial interventions.” This report places the patient at the center of a
process to identify outcomes that are important, research methods that identify
key elements of interventions, and translation efforts that ensure fidelity.
Another NAM report on SUDs, titled Substance Use Disorders in the U.S.
Armed Forces, recognizes the effect of combat on substance use among veterans
(8). The NAM committee found substance use and misuse in the military have
increased and now represent a significant public health problem; however, their
focus excluded an exploration of tobacco use in the military which is also a
significant health issue. The leading causes for concern are elevated rates of
unhealthy alcohol use (33% of active duty military screen positive for alcohol
use risk on the Alcohol Use Disorders Identification Test or AUDIT), binge
drinking (47% of active duty service members report drinking five or more
drinks at least once in the past month), increased nonmedical use of prescription
analgesics (rate was 2% in 2002 and 11% in 2008), and high opioid prescription
rates (military physicians wrote more than four times as many opioid
prescriptions in 2009 as they did in 2001). The report strongly recommends the
full implementation of the Department of Defense evidence-based guideline for
treating SUDs—specifically, that the Department of Defense increases their use
of evidence-based practices to consistently implement prevention, screening,
diagnosis, and treatment services. In addition, the report exposes some of the
barriers to care that currently exist in the military. To address these systemic
barriers to care, the NAM recommendations include (a) enhancing the use of
technology, (b) providing confidential care, (c) making greater use of continuing
care, (d) expanding access to care, and (e) creating a 21st century workforce (8).
One important common theme that carried across all five NAM reports on
quality is that system design, reimbursement processes, and service delivery
have more impact on treatment results (patient outcomes) than variation in
individual practitioner knowledge or behavior. In other words, improved
outcomes will come more readily from improved research and delivery systems
than from additional training. Though human resource development is important,
better system design trumps improvement of skills as a leverage point for
improving outcomes for populations (9).
In November 2016, the Surgeon General released the report Facing
Addiction: The Surgeon General’s Report on Alcohol, Drugs, and Health,
presenting “a call to action to end the public health crisis of addiction” (10). The
report calls for more fully integrating SUD treatment with the healthcare
delivery system to improve both access and quality. It also calls for the treatment
system to increase the adoption of health information technologies including
electronic health records, clinical decision support systems, and patient support
mobile apps to increase data-driven decision-making and improve patient and
population outcomes. Other recommendations related to quality improvement
include the wider use of medications to treat alcohol and opioid use disorders
and greater adoption of evidence-based psychosocial interventions.
DEFINING AND MEASURING QUALITY

TREATMENT AND OUTCOMES
Public expectations, demands for accountability from payers and policy makers,
and a strong desire from within the field of addiction medicine to improve
performance drive efforts to define and measure effective treatments and
treatment outcomes. Measurement is a key to improvement. Measures of
performance before and after the introduction of changes enable managers to
verify desired impacts and to monitor, track, and maintain performance over
time. The National Committee for Quality Assurance (NCQA), National Quality
Forum (NQF), and payers (e.g., SAMHSA and its Center for Substance Abuse
Treatment [CSAT], Veterans Health Administration [VHA], and state and county
governments) collaborate with researchers, treatment providers, and professional
trade groups to construct and evaluate measurement systems and to promote
quality improvements. Their efforts to define and measure the quality of
addiction treatment resulted in the development of measures that track system
performance (ie, Washington Circle [WC], Healthcare Effectiveness Data and
Information Set [HEDIS], and NQF measures). Utilizing these measures,
practitioners and researchers seek to understand the relationship to client
outcomes and identify the prevalence of substance use within specific
populations like the VHA. Efforts by the NQF and the American Society of
Addiction Medicine (ASAM) seek to standardize care via the use of process
measures that are assumed to link to outcomes.
Measuring Performance in Addiction

Treatment Providers
The CSAT has provided support to the WC Group to develop and test process
measures that monitor the performance of health plans and public treatment
systems. To date, a total of six measures have been developed and evaluated in
the field (11,12). Additional continuity of care process measures (post–
withdrawal management, aftercare, and residential treatment) was developed and
evaluated to assess continued client engagement in treatment post discharge
from a different level of care (13). In the past 2 years, the NQF has endorsed ten
different measures for SUDs and is evaluating three ASAM- and American
Medical Association (AMA)-sponsored measures (14). Table 34-2 shows the
definitions of the WC and NQF measures.
TABLE 34-2 Washington Circle and National Quality

Forum Measure Definitions
The WC initiation and engagement process measures are included in the HEDIS
measures that health plans submit annually to the National Commission for
Quality Improvement. Evaluation of the HEDIS and WC measures reveals
differing levels of initiation and engagement by level of care and by type of plan
(11,12). In addition, the adoption and use of these measures by Single State
Authorities for addiction treatment show variability in state capacity to calculate
these measures and variation in the measures across states (15).
Studies of the WC measures typically explore the relationship between the
measures and selected societal or treatment outcomes. For example, an analysis
of administrative data from Oklahoma found that individuals who initiated and
engaged in treatment for SUDs were less likely to be arrested or incarcerated
(16). In another study involving adolescent treatment agencies, continuity of care
postresidential treatment potentially predicts 3-month recovery; adolescents who
engage in treatment had lower likelihoods of reporting any substance use,
alcohol or heavy alcohol use, and marijuana use (17–19). The proximal process
measures seem to anticipate improvements on distal outcome measures. The
impact of WC initiation and engagement measures also shows initial promise in
exploring chronic disease management care for addiction (20). In another study,
community health centers (CHCs) offering intensive outpatient treatment
showed greater client engagement in treatment than CHCs offering only
screening and/or counseling (21). However, receipt of care under an alternative
quality contract introduced by the Center for Medicaid and Medicare Services
and Center for Medicaid and Medicare Innovation (CMMI) found no significant
increase in treatment initiation or engagement (22).
Veterans Health Administration

A VHA study exploring the probability of patients advancing to treatment
initiation and engagement given the initial setting of presentation found that 25%
of initiation and 40% of engagement occurred outside of a specialty care setting.
However, patients presenting in specialty settings have higher rates of initiating
treatment, and once initiated, to engage in further treatment than patients who
present in nonspecialty care settings (23). The VHA also examined relationships
between center performance on WC initiation and engagement measures and
improvements in patient outcomes. Study results are mixed. For example, one
study found no significant influence: better rates of identification, initiation, and
engagement were not related to greater improvement on outcomes as measured
by the Addiction Severity Index (ASI) (24). Another study compared the VHA
continuity of care and the HEDIS engagement measure and found that
improvement in ASI measures was associated with the HEDIS but not the VHA
measure (25,26). Conversely, the WC continuity of care measure was associated
with a significantly lower mortality rate (27).
In terms of access to medications for alcohol use disorders, a study in the
VHA found that the percent of patients receiving at least one approved
medication for treatment of alcohol dependence (acamprosate, oral and
injectable naltrexone, or disulfiram) was 3.4% in 2009 and patients who received
a medication and had a visit to addiction specialty treatment was 8.2% of
patients in 2009 (28,29). The study also found variations in the overall
prescribing rates by facility. The results from these studies (a) highlight the
importance of clearly defining and agreeing to measures before embarking on
quality improvement efforts, (b) provide evidence that similar measures may
yield different results, (c) suggest that these measures should be used to assess
facility performance not quality of care, (d) highlight the importance of
treatment integration within the VHA, and (e) indicate that the use of alcohol
and opioid use disorder medications are still not widespread in the VHA
addiction treatment system.
However, these studies rely on analysis of administrative data and are not
measuring the impact of quality improvement initiatives on levels of initiation
and engagement or their relationship to patient outcomes. Improvements in
initiation and engagement in treatment in some cases may have little to do with
the physician’s knowledge of addiction but are instead related to organizational
issues involving the intake process, eligibility requirements, access to treatment
on demand, convenient office hours and transportation, or efforts to adequately
engage patients in the ongoing treatment process (30–32). To address these
issues, it is important to explore existing processes and implement system
changes that enhance these outcomes. For example, a provider could offer
“minimal treatment” or “interim maintenance” for opioid treatment program
waiting lists, examine and improve their existing paperwork process, or offer
walk-in appointments to clients. Other promising practice examples can be
found through the NIATx or Agency for Healthcare Research and Quality
(AHRQ) Practice-Based Research Network (PBRN) websites.
There is a lack of consensus on what appropriate outcomes for addiction
treatment should be. Research may measure reduced use in a variety of ways
such as number of days using or abstinence versus use (33,34) or other outcomes
such as criminal justice involvement (35). Recently, there has been an effort to
develop measures of recovery (36,37). SAMHSA is currently piloting a recovery
outcome measurement tool in its discretionary portfolio. In 2016, SAMHSA
began a process to develop consensus on an appropriate outcome measure to
assess the treatment system’s efficacy at the population health level. A consensus
panel comprised of researchers, practitioners, and payers, both public and
private, met to identify potential outcome measures that could be used by
stakeholders to assess individual- and population-level outcomes. Debate
continues on whether the outcome of treatment should be measured by symptom
reduction, reduction or cessation of use or other behaviors related to substance
use, or improvement in quality of life as defined by the concept of recovery.
Until there is resolution, practitioners will continue to rely on process measures
such as access to care and continuation in care as proxies for appropriate
outcomes.
National Quality Forum

The NQF is a congressionally chartered membership organization charged with
using empirically based consensus process to define and disseminate standards
and measures for the healthcare system. The federal Office of Management and
Budget directs federal agencies (e.g., the Centers for Medicare and Medicaid
Service) to use voluntary consensus standards in lieu of government-unique
standards in procurement and regulatory matters. A recent NQF report, National
Voluntary Consensus Standards for the Treatment of Substance Use Conditions,
identifies 11 treatment practices, organized into four domains and subdomains,
as evidence-based strategies for addressing SUDs (38). Table 34-3 summarizes
the domains and subdomains.
TABLE 34-3 Summary of NQF Consensus Standards

for the Treatment of Substance Use Conditions
The endorsement of these practices by the NQF’s members (more than 437
organizations, including healthcare providers, consumer groups, professional
associations, purchasers, federal and state agencies, research and quality
improvement organizations, and suppliers) is the first formal consensus on
evidence-based practices for treatment of SUDs. While follow-up work
continues to define, test, and disseminate operational measures for the NQF-
sanctioned practices, the impact in the fields of mental health and SUD care is
minimal compared to other healthcare settings (39). The NQF standards for
initiation and engagement have been included as continuous quality measures
that are to be reported by eligible professionals (beginning in 2014) in order to
receive incentive payments or avoid penalties in the final rule for stage two
criteria for the meaningful use of electronic health record systems (40). The
NQF is also exploring the development of measures and an associated
framework intended to address the multiple chronic conditions present in many
individuals seeking treatment for these conditions (41).
ASAM Standard Workgroup
The ASAM work has released two reports: Standards of Care for the Addiction
Specialist Physician and Performance Measures for the Addiction Specialist
Physician. These documents outline the standards of care and how to measure
performance in meeting the standards for addiction specialists. The standards
cover the activities expected to be conducted for diagnosis, withdrawal
management, treatment planning and management, continuing care and
transitions, and care coordination (42,43).
Certification of Office-Based Opioid

Treatment Providers
The Drug Addiction Treatment Act, passed in 2000 (DATA 2000), permitted
physicians to obtain a waiver from the separate registration requirements of the
1974 Narcotic Addict Treatment Act to treat opioid use disorder with Schedule
III, IV, and V medications or combinations of such medications that have been
approved by the US Food and Drug Administration (FDA) for that indication.
Currently the only medication that meets these criteria is buprenorphine.
Physicians must demonstrate that they have completed an 8-hour course on the
treatment of opioid use disorder in order to receive a waiver that allows them to
treat 30 patients. After a year of holding a 30-patient waiver, a physician may
apply to treat up to 100 patients. Regulations passed in 2016 allow a physician to
apply to treat up to 275 patients after a year of holding a 100-patient waiver. The
275-patient waiver requires physicians to submit an annual report to SAMHSA
on the number of patients treated and the diversion control activities of the
practice. The passage of the 2016 Comprehensive Addiction and Recovery Act
(CARA) amended DATA 2000 to include nurse practitioners (NPs) and
physicians’ assistants (PAs) who are acting within their state license to lawfully
prescribe controlled substances. However NPs and PAs must complete 24 hours
of training rather than the 8 required for physicians. Since its enactment, nearly
40,000 physicians have obtained a waiver under DATA 2000. As of this writing,
NPs and PAs have just begun to be able to apply for a waiver, and over 150 had
applied in the first 2 weeks. While the passage of DATA 2000 and CARA may
greatly expand access to care, oversight of these new prescribers is primarily left
to state licensing boards rather than accreditation bodies and the federal
government.
ACCREDITATION FOR TREATMENT
PROGRAMS
Performance measures are often examined in accreditation reviews.
Accreditation is recognition by peers that an organization meets standards of
performance that represent safe and competent treatment. Three bodies—the
Joint Commission (TJC), the Commission on Accreditation of Rehabilitation
Facilities (CARF), and the Council on Accreditation for Children and Family
Services (COA)—are the primary entities that provide peer-reviewed
accreditation for addiction treatment programs (44). The 2013 National Survey
of Substance Abuse Treatment Services (N-SSATS) notes that approximately
55% of the facilities reported accreditation from TJC (18%), CARF (24%), COA
(5%), state or local agency (4%), or NCQA (3%) (45).
Accreditation Process
Accreditation requires an organization to conduct an extensive internal analysis
of its performance. Accreditation standards focus on broad domains, including
governance, consumer rights and privacy, human resource development, the use
of treatment and/or clinical interventions, methods to continually improve
quality, maintenance and use of records, business systems, and facilities. The
standards are aimed at minimum to promote patient safety and optimally to
improve patient outcomes. The organizational self-analysis is followed by a site
visit by peers or accreditation surveyors, who independently verify the existence
and performance of components noted in the self-assessment. Surveyors identify
strengths and the need for improvement and then present a recommendation to
the accrediting body for multiyear, limited, conditional, or denial of
accreditation.
Accreditations for Opioid Treatment

Programs
An exception to the limited accreditation of treatment programs are outpatient
opioid treatment programs. As a result of a transfer of authority from the FDA to
SAMHSA in 2001, federal regulations (42 CFR Part 8) require that opioid
treatment programs receive certification from a national accreditation
organization or state agency documenting that the treatment program meets
regulatory standards and will comply with the standards. Recently published
guidelines require opioid treatment programs to have a current and valid
accreditation, SAMHSA certification, and Drug Enforcement Administration
registration before dispensing opioid medications (46). There are six approved
accrediting bodies including CARF, TJC, and COA as well as the National
Commission on Correctional Health Care, the Healthcare Facilities
Accreditation Program, and two states. They review opioid treatment programs
to confirm that the services comply with federal standards, including the
elements found in regular accreditation reviews and some specific to opioid
treatment services: specialized services for pregnant patients, HIV counseling
and education, and procedures to dispense medications in compliance with
federal rules (46).
Evaluating Policy Impact on Treatment

The CSAT conducted an evaluation of the shift from an enforcement model
administered by the FDA to a regulatory model administered by the CSAT and
carried out by approved accrediting bodies that was published in 2006 (47).
Eighty-six percent of programs that responded to a survey conducted as part of
the evaluation reported that accreditation improved their service quality. Survey
respondents identified improved quality assurance activities as the single largest
effect of the shift from enforcement to accreditation.
A 2016 task force evaluation of whether insurers were following the 2008
Mental Health Parity and Addiction Equity Act (MHPAEA) (48) and the
Affordable Care Act (ACA) (49) found that the primary violations of the two
laws that limit access to services and medications for SUD are what are called
“nonquantitative treatment limits,” such as requirements to fail in outpatient
counseling before being able to obtain medication or residential treatment
services or prior authorization requirements that are different from those for
other health conditions (50). Federal government limits, such as the institute of
mental diseases limit on the use of Medicaid to reimburse for inpatient
psychiatric or SUD treatment, were also raised, and as a result, there are efforts
underway to allow for waivers for reimbursement of short-term inpatient care for
emergency purposes.
BUILDING SYSTEM CAPACITY TO

DELIVER EFFECTIVE TREATMENTS
Since 2001, a number of national-level efforts have focused on improving the
quality of treatment offered, particularly among the block grant-funded
programs. Contemporary quality improvement strategies begin with recognition
that insufficient quality often reflects poor system and process design. As in
other industries, process improvement strategies in addiction treatment strive to
construct processes that minimize variability and eliminate error to improve
efficiency and enhance customer satisfaction with the product or service.
Shewhart (51,52) and his students Deming (53) and Juran (54) were pioneers in
the application of these techniques to manufacturing. Over time, the concepts
have been extended to service industries including health care (55,56).
The NIATx Model of Process Improvement

NIATx (an acronym derived from its origins as the Network for the
Improvement of Addiction Treatment) is the primary mechanism that has been
used to apply process improvement strategies to the programs that treat alcohol
and drug disorders. Change teams within participating organizations learn to use
process improvement tools and techniques to meet the WC measures including
reduced time to admission, decreased no-shows, enhanced retention in care,
increased admissions, and increased use of evidence-based practices (57,58).
Five key process improvement principles have been identified through meta-
analysis to facilitate organizational changes to enhance the quality of addiction
treatment services: understanding the customer, fixing key problems, picking a
powerful change leader, seeking outside ideas and encouragement, and using
rapid Plan, Do, Study, Act (PDSA) cycles (59,60). Together, these principles
have the potential to influence organizational culture and reflect an orientation to
continuous improvement. The use of the NIATx approach for quality
improvement is also applicable for providers as they seek to address the NAM
six dimensions of care (61).
Understand the Customer

Process improvement stresses the need to understand and involve customers in
identifying and fixing problems. Focus groups and interviews with clients can
help increase understanding of treatment experiences. Another useful tool is the
walk-through; observers simulate the patient experience and participate in the
processes that are required for patients, documenting their experiences. Change
leaders use a walk-through to gain insight into problems in treatment processes.
Walk-through protocols typically start with the admission process. A senior
manager develops a patient script (description of the patient and the presenting
problems), calls the treatment center for an appointment, completes the
admission process, and notes positive and negative findings. Typically, the walk-
through scenario includes a “family member” (e.g., sister, spouse, or parent) who
shares the experience and makes additional observations. Individuals who
conduct the walk-through should record notes both expected and unexpected
about all stages of the experience (e.g., initial assessment, first treatment session)
and identify what surprised them as well as opportunities for improvement. For
example, the front office staff was friendly and efficient, or the intake process
involved multiple steps with redundant paperwork. As part of the walk-through
process, they should ask other staff about their ideas to change or improve the
process. These walk-through notes create stories with impact and illuminate
problematic facets of the process that can then be addressed in process
improvement protocols.
A review of walk-through reports from 327 applicants of NIATx projects
revealed a number of issue treatment programs needed to improve including
conflicting and incorrect information to patients, redundant and burdensome
intake forms, unanswered telephone lines, and unreturned voice mails (60).
There were also challenges addressing complex patient needs (such as co-
occurring disorders) and weaknesses in agency infrastructure (62). Change teams
use the results of walk-through to identify process problems that can be
corrected and improved.
Fix Key Problems

Agency change requires active support from the highest levels of the
organization. The chief executive will often be supportive of change that
addresses issues that affect revenue and costs (63). Missed appointments, for
example, reduce counselor productivity, and anticipated revenue is lost.
Strategies to reduce no-show rates, therefore, can lead to increased revenues and
improved counselor productivity.
Phoenix Center in Greenville, South Carolina, for example, completed a
walk-through and found that they had a waiting list for withdrawal management
beds at the same time as having five empty beds. To reduce the waiting list and
fill the beds, the program implemented a series of change cycles. The specific
changes were to eliminate scheduled withdrawal management admission
appointment, reduce phone screen questions, adjust staff schedules during peak
admission times, post bed availability, and ask clients “What time can you be
here today” versus “We have an appointment available on.” As a result of the
change, bed utilization increased 10% from 90% to 99%, and monthly program
revenues increased by 11%. In another example, the Aegis Medical System that
operates 25 opioid treatment programs across California conducted a walk-
through of the admission process. The results found that the first appointment,
which included paperwork and a medical assessment, lasted 4 hours and the first
clinical intervention was scheduled for 1-3 weeks later. They also analyzed 17
months of discharge data and set as a goal to reduce the first 90-day attrition rate
by 10% over a 6-month period. The staff tested a change called “Five in Five”
where the client had their medical assessment on day one and then on 4
subsequent days met with the clinician to tell their story and establish a
relationship. As a result of the change, the attrition rate fell by 75% from 16% to
4% in 2 months with a projected increase in the annual revenue of $388,000. The
change was diffused to all Aegis opioid treatment programs.
Pick a Powerful Change Leader

The change leader (the individual who leads a team in creating and
implementing organizational change) is an integral part of the successful change
effort in the organization. It can also be an excellent career development
opportunity. To help prepare individuals, NIATx developed a Change Leader
Academy designed to teach the skills to become an effective change leader (64).
Not every counselor or employee, however, has the skill to lead change, and
many do not seek the responsibility of leading change. It is important, therefore,
to choose individuals with the right mix of aptitude and ability. Change leaders
should have the respect of their peers and of staff and leaders throughout the
organization. They must also have access to agency management. Within the
organization, the change leader is responsible for running the change team
meetings, and as such, they should have effective project management skills
including being organized, a good delegator, and comfortable with using data to
guide improvement efforts. Over time, a well-developed organization will use
the opportunity to lead change teams as a strategy for grooming future managers
and leaders within the organization.
Seek Outside Ideas and Encouragement

NIATx members get ideas for service improvements from other NIATx
participants and from other industries. The vice president of quality
improvement at the Ritz Carlton spoke at a NIATx conference and shared his
perspectives on serving hotel guests and the hotel’s expectations for customer
orientation among all employees: “Ladies and Gentlemen Serving Ladies and
Gentlemen.” Though the Ritz typically serves a clientele different from that
found in most publicly funded substance use treatment services, its emphasis on
treating guests and staff as ladies and gentlemen can be applied in any business,
including addiction treatment. Opportunities to learn from others are not limited
to the hospitality field. For example, an organization might be able to learn from
a local car dealer how to engage clients, from an air traffic control how to hand-
off clients within or across organizations, or from retailers who open up new
lines when the queue gets too long. Leveraging these ideas requires an ability to
think outside the box, recognize that other organizations experience similar
problems, and adapt those solutions to the specific situation in their organization.
Use Rapid Plan, Do, Study, Act Cycles

PDSA cycles are a central component of process improvement. Planning
includes specification of the problem that will be fixed, collection of data to
assess the extent of the problem, and development of a change that will be
implemented. Process improvement is about action. Change teams test the
proposed change (do). A key facet is that the test is for a limited time and limited
number of patients. Initially, it is a feasibility test. Can we make the change, and
does the change produce the desire effect? A few simple measures are collected
and analyzed (study): did a change occur in the frequency or extent of the
problem? Based on the planning, doing, and studying, the change team decides
what to do next (act). The change can be abandoned if it does not work. It may
be modified to enhance the effect. If the pilot was successful, it expands to
include more patients and more counselors or more sites and, eventually, is
institutionalized through changed policy and procedure manuals. PDSA cycles
are rapid. Two weeks or less is usually sufficient to learn whether the change is
viable and if additional time and resources should be invested.
Analysis of admissions data from the first cohort of NIATx participants over
a 15-month reporting period found a 37% decline in days to treatment, from
about 20 days in October 2003 to 12 days in December 2004 (58). Significant
improvements were also observed in retention in care. In October 2003, about
72% of the patients who completed one unit of care returned for a second unit of
care; by December 2004, 85% of the admissions received at least two units of
care (58). Further analysis with a second cohort of NIATx participants replicated
these findings and showed that participants from the first cohort sustained the
improvements (65). Although gains may appear to be modest, the impact of
process improvement seemed to increase over time, and preliminary analyses
suggest that programs can sustain the improvements in access and retention.
Additional analysis of NIATx data suggests that reduction in days to treatment
enhances the likelihood that individuals will complete four treatment sessions
(66). The learning community promotes collaborative opportunities for
participants to learn from each other. Analysis shows that small, localized
learning communities are effective at reducing wait time and improving adoption
of evidence-based practices (67,68). Finally, qualitative analyses of NIATx
implementation highlighted the relative ease within organizations of
implementing the NIATx process improvement model (69), while some
programs struggled with the development of change measures and use of process
data (70).
NIATx 200
Due to the success of the initial NIATx program, the National Institute on Drug
Abuse subsequently funded a randomized trial in which 201 treatment programs
in Massachusetts, Michigan, New York, Oregon, and Washington State
participated in activities designed to assess the key elements of NIATx training.
The programs were randomly assigned to four different levels of NIATx support
in an effort to understand if particular components worked better than others: (a)
interest circle telephone calls plus access to the NIATx website, (b) coaching
plus access to the NIATx website, (c) learning sessions plus access to the NIATx
website, and (d) interest circle telephone calls, coaching, and learning sessions
plus access to the NIATx website (71).
Analyses assessed the influence of each study condition on change in days to
treatment and retention in care. Results indicate that wait time significantly
improved over a 14-month period for each level of support except interest circle
calls (72). Providers in the coaching support saw a 4.6 days/clinic reduction in
wait time versus 3.5 days/clinic reduction in the learning session and a 4.7
days/clinic reduction in the combination intervention. None of the levels of
support resulted in a significant improvement in continuation defined as the
percent of clients retained from the first to fourth treatment session. Providers in
the coaching and combination levels of support significantly increased the
number of new patients—19.5% (coaching) and 8.9% (combination),
respectively. A calculation of the benefit–cost ratios found that the coaching
level of support was more cost-effective than the learning session or combination
supports at reducing wait time or improving the number of new patients.
Additional research found that agencies were able to reduce the time from the
first contact to the first appointment by an average of 1.4 days (73) and that
better managed programs had significantly shorter wait times (74). Findings
from the NIATx 200 study further suggest that NIATx is an effective process
improvement technology that can help improve certain aspects of the treatment
systems for alcohol, drug, and mental health disorders.
Advancing Recovery
Advancing Recovery, sponsored by the Robert Wood Johnson Foundation,
invited states and providers to collaborate and facilitate the implementation of
evidence-based practices for the treatment of SUDs. The project was designed to
promote implementation of the NQF’s five sets of evidence-based practices: (a)
use of medications, (b) screening and brief interventions in primary care settings,
(c) seven psychosocial interventions (motivational interviewing, motivational
enhancement therapy, cognitive behavioral therapy, structured family therapy,
contingency management, community reinforcement, and 12-step facilitation),
(d) posttreatment aftercare, and (e) case management, wraparound, and
supportive services. Participating states (Alabama, Arkansas, Colorado,
Delaware, Florida, Kentucky, Maine, Missouri, Rhode Island, and West Virginia)
and cities (Baltimore and Dallas) made changes in systems to support and
encourage the use of these categories of treatment services. A model of change
emerged from the Advancing Recovery experience to guide the change efforts
and provide structure for state and provider initiatives (75). The model
articulates four specific conditions, five levers, and three supports for change.
Participants used a variety of strategies to achieve their goals, yet all relied on
incremental testing to achieve results, which found that the rate of medication
adoption was higher than continuing care management (69). This study led to
two randomized trials of the model specifically to support the adoption of
medication assisted treatment. A county-based payer provider-level intervention
examined the use of the model to increase access to buprenorphine (76).
Interviews with county and provider staff identified facilitators (e.g., knowledge
of medication benefits) and barriers (e.g., attitudes toward the use of
medications) impacting successful implementation (77). A second study is
exploring the application of the Advancing Recovery model in a national health
plan. Patients in the intervention clinics were more likely to receive an alcohol or
opioid medication than patients in the comparison clinics (78). A qualitative
analysis utilized the Consolidated Framework for Implementation Research to
identify the characteristics of injectable extended-release naltrexone as well as
inner and outer setting barriers to implementation (79).
ENSURING PRIMARY CARE

PROVIDERS CAN IDENTIFY, TREAT OR
REFER, AND MONITOR SUBSTANCE
USE DISORDER
There is an increasing recognition that general medical practitioners should be
able to screen for and monitor and provide medication for SUDs. A study found
a high prevalence of alcohol (60%) and drug use (5%) among patients of
primary care practices; among the drinkers, one in five (22%) had either an “at-
risk” pattern of use or an alcohol-related health problem (80). Patients with
SUDs have a higher prevalence of heart, liver, and gastrointestinal disorders
(81). Specialty addiction treatment centers developed because medical care was
not addressing patient’s SUDs. However, primary healthcare workers regularly
see patients who have (or risk having) a substance use problem or health
conditions that are exacerbated by substance use.
The separation of treatment for medical and behavioral illness is an area that
is increasingly being addressed. For example, the White House Office of
National Drug Control Policy (ONDCP) 2015 National Drug Control Strategy
asserts that SUDs are medical conditions and that treatment should be integrated
into mainstream health care and suggests concrete steps toward the goal of
improved access to addiction treatment services (82), including the integration of
Screening, Brief Intervention, and Referral to Treatment (SBIRT) into all
healthcare settings. At its core, SBIRT has three goals: (a) screening to rapidly
assess the severity of substance use and identify the appropriate level of
treatment, (b) a brief intervention that focuses on increasing insight and
awareness regarding substance use and motivation toward behavioral change,
and (c) referral to specialty treatment (83). The Health Resources and Services
Administration has taken steps to promote the use of screening services, such as
including codes for BI in the Uniform Data Systems to track screening activity
in Federally Qualified Health Centers. States are encouraged to adopt SBIRT as
a reimbursable service and train more service providers in SBIRT. Lastly, the
ONDCP strategy also stressed the importance of screening and early intervention
in women’s healthcare settings, as this has the potential to reduce the estimated
400,000 to 440,000 infants affected by prenatal alcohol or illicit drug exposure.
Although there has been some movement to offer primary care services in
addiction specialty clinics, the ONDCP Strategy reflects the general trend in
policy and resources into primary care settings rather than the other way around.
An advantage to this arrangement concerns the reduction in the stigma that may
occur for individuals obtaining SUD treatment from a primary healthcare
provider, compared to a stand-alone specialized service. Many doctors are not
trained in how to identify or treat addiction. But with new research into how it
affects the body and the brain, more doctors are coming to an understanding of
addiction as a medical problem and addressing it as a chronic disease. Until
recently, there have been no national standards for training in addiction
medicine, and medical students receive little addiction training. In 2016, the
American Board of Medical Specialties recognized addiction medicine as a new
subspecialty under the American Board of Preventative Medicine. This will
replace the American Board of Addiction Medicine (ABAM) subspecialty
process for becoming certified in Addiction Medicine. The two boards are
currently working to transition the process and ensure that doctors are equipped
with the necessary knowledge and skills to provide specialty care for people with
gambling and SUDs.
These same specialty boards require that physicians at the time of
recertification and licensing requirements implement a performance in practice
project (84,85). Launched in 2006, the Improving Performance in Practice
initiative uses quality improvement tools and techniques including PDSA cycles
designed to improve processes of care. The tools and techniques outlined in this
chapter provide an approach that physicians could use to achieve their
maintenance of certification requirements. Results from a recent study suggest
that addiction psychiatrists can leverage the Maintenance of Certification
process to improve clinical care (86).
There are a number of tools for physicians to ensure quality in office-based
addiction treatment. The CSAT offers Treatment Improvement Protocols (TIPs),
three of which are for prescribers treating either alcohol or opioid addiction
(87–89). Each of these manuals comes with a Knowledge Application Program
(KAP) Key that is a short version of the critical clinical information outlined in
the TIP. In 2017, TIP 40 (on guidelines for prescribing buprenorphine) and TIP
43 (on medication use in opioid treatment programs) will be combined into one
manual and updated to include the new formulations of medications recently
made available.
Buprenorphine prescribing requires an 8-hour training and an application for
a waiver from the Drug Enforcement Administration. The Provider’s Clinical
Support System for Medication Assisted Treatment (PCSS-MAT) provides these
physicians with training, support, and mentoring in treating patients with opioid
use disorder using medication. The training, waiver process, and PCSS-MAT are
all part of an effort to ensure quality in the treatment of patients with opioid use
disorder (90). While the training is required only for those seeking to prescribe
buprenorphine, all three currently available medications (methadone,
buprenorphine, and naltrexone) are included so that practitioners are
knowledgeable about the choices available to their patients and the rationale for
prescribing one medication over another for specific patients.
One final tool that is being used increasingly by physicians in primary care
who wish to treat patients with SUDs is prescription drug monitoring programs
(PDMPs). In all states but one, PDMPs provide physicians with timely
information on the scheduled drugs their patients have been prescribed by other
physicians as well as themselves. Requesting data from the PDMP on
prescriptions filled by a patient with SUDs, in addition to drug testing, can serve
as a risk management tool but also as a quality management tool. Treatment may
need to be adjusted if patients are not filling their prescriptions or are on multiple
medications prescribed by other medical professionals.
The use of medications to treat SUDs needs to continue to be integrated into
the treatment system at a faster pace and for more patients. The pace that
changes are made will be impacted by individuals’ ability to pay and payers’
willingness to include these medications and services in their plans.
INTERNATIONAL EFFORTS: THE

INTERNATIONAL CENTER FOR
CREDENTIALING AND EDUCATION OF
ADDICTION PROFESSIONALS
Established in February 2009, the International Center for Credentialing and
Education of Addiction Professionals (ICCE) is a global initiative funded by the
Bureau of International Narcotics and Law Enforcement Affairs (INL), US
Department of State. ICCE’s mission is to train, professionalize, and expand the
drug demand reduction workforce globally. ICCE was formed in response to
inadequate evidence-based programs and lack of trained addiction professionals.
It is an international certified education provider of the US National Association
of Alcohol and Drug Abuse Counselors (NAADAC).
ICCE collaborates with international experts to develop training curricula in
the areas of substance use prevention and the treatment of SUDs. The Universal
Prevention Curricula and the Universal Treatment Curricula are multi-module
training programs designed to equip prevention and addiction treatment
professionals with knowledge, skills, and competencies to efficiently deliver
drug demand reduction services. Both the UPC and UTC are developed by a
team of experts in the field and approved by three international organizations,
namely, United Nations Office on Drugs and Crime (UNODC), Organization of
American States (OAS), and Colombo Plan. Each curriculum is piloted, adapted,
and adopted by the region or country implementing the initiative. The
curriculum content of the UPC and UTC has been found to meet the national and
international certification standards set by the US National Certification
Commission of Addiction Professionals (NCCAP).
CONCLUSIONS
Quality improvement efforts are affecting the organization and delivery of
treatment for gambling and SUDs. These efforts should include a focus ensuring
that the care delivered is consistent with the NAM’s six dimensions of quality.
Strategies to define, measure, and improve the quality of addiction treatment
services influence standards of care and the ways in which quality is evaluated.
Quality interventions that build on the foundation of the NIATx model may be
especially promising and have a growing body of research that supports them.
Treatment programs engaged in NIATx gain encouragement and ideas from
participation in learning communities and support the application of process
improvement to systems of care for these disorders. Outcome studies suggest
that process changes can lead to reductions in days to admission and to
improvements in retention in care. NIATx change initiatives have many
advantages and the key resources needed to widely spread and sustain changes.
The NIATx approach also attempts to promote a spread of process
improvements across statewide treatment systems. The key NIATx principles of
change work for individual organizations and are also applicable to multi-
organizational system changes to facilitate adoption of evidence-based practices.
Advancing Recovery is another effort to spread system change through an
explicit focus on changes in state regulations and financing to sustain and spread
process improvements and evidence-based practices. Additional principles,
however, also need to be considered when addressing statewide
adaptations/changes not only at the provider and Single State Authority level but
within other state agencies such as Medicaid and Youth and Families. Formal
working relationships, for example, need to be established between organizations
when large-scale system changes are planned.
Continuing medical education is evolving to be more practice oriented in
general, focusing less on information provision and more on supporting change
in practice and development of skills. As physicians are asked to demonstrate
their ability to institute change and ensure quality treatment, demonstration of
the use of the tools of quality management including the institutionalization of
quality improvement mechanism becomes an essential component of a medical
practice.
While we have not specifically addressed technology, it is a growing factor
in ensuring consistency in practice. There are many efforts to automate and
streamline service delivery: computer-based screening and brief interventions,
mobile phone applications for relapse prevention, development of predictive
models that use real-time data from sensors or ecological momentary
assessments, and the use of games to increase engagement in the recovery
process. In addition, payers are increasingly using tele-counseling services in an
effort to comply with requirements for adequate availability of services even to
members in remote locations. These leaps forward are dramatically changing the
landscape of addiction care and shifting the criteria for defining quality as well
as the way we measure it.
ACKNOWLEDGMENTS
We would like to acknowledge the initial contributions of Dr. Dennis McCarty,
Dr. Victor Capoccia, and Dr. David Gustafson, whose works in previous editions
of the Principles of Addiction Medicine provided the foundational basis upon
which we developed our chapter. We also would like to thank Dr. Corey Waller
and Judith Martin for their thoughtful review and comments regarding
improvements to this chapter.
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CHAPTER 35
Nursing Roles in Addressing Addiction
Deborah S. Finnell, Marianne T. Marcus and Christine L.
Savage
CHAPTER OUTLINE
Introduction
History of Development of Nursing Roles in Addiction Care
Current Trends in Substance Use
Levels of Nursing Education and Practice
Generalist’s Roles Related to Addiction
The Addiction Nurse
Addiction Nursing Workforce
INTRODUCTION
Nurses constitute the largest segment of the healthcare workforce. According to
the last comprehensive survey in 2008, there were 3.1 million registered nurses
(RNs) in the United States, 85% of whom are employed in nursing (1).
Moreover, nurses are typically the first point of contact for patients entering
diverse healthcare environments and likely to have sustained close contact with
patients and families. The American Nurses Association (ANA) defines nursing
as the “protection, promotion, and optimization of health and abilities,
prevention of illness and injury, alleviation of suffering through the diagnosis
and treatment of human response, and advocacy in the care of individuals,
families, communities, and populations” (2). This broad definition supports a
comprehensive role in prevention, detection, and treatment of health problems,
competencies that are critical for addressing the health challenges associated
with substance use and substance use disorder. Nurses are prepared to be patient
educators who support and encourage behavior change to improve health.
Professional characteristics such as sustained patient contact and preparation as
educators support a mandate for a comprehensive nursing role in addressing
substance use and substance use disorder at all levels of practice and in all
healthcare settings (3). This chapter examines levels of nursing education and
practice and the various roles nurses have as generalists and advanced
practitioners with a particular focus on addiction nursing. Practice competencies,
standards, certification requirements, and the professional organization that
supports and governs the nursing role in addressing the continuum of substance
use and health will be explicated.
HISTORY OF DEVELOPMENT OF
NURSING ROLES IN ADDICTION CARE
Content on alcohol and associated health risks and recommended nursing care of
late-stage alcohol use disorder first appeared in nursing textbooks in the 1950s
(4). Federal funding increased nursing education for this important area of
practice beginning in the 1970s. In 1972, the National Institute on Alcohol
Abuse and Alcoholism (NIAAA) funded alcohol-related nursing traineeships for
undergraduate and graduate students at the University of Washington (5). Estes
and Heinemann (6) published a definitive nursing text on alcoholism in 1977,
again, addressing alcohol use with sections on diagnosis, alcohol consequences
on body systems, alcohol problems in special populations, and interventions.
Despite these national efforts, translation of content related to the prevention
and treatment of substance use disorders into nursing curricula did not occur
across schools of nursing and, when included, only minimally. An early national
survey of substance use in nursing curricula revealed that content was confined
to care of patients with substance use disorders and was taught mainly in
psychiatric mental health courses (7). From these early beginnings, the nursing
profession made progress toward setting practice standards related to substance
use disorders (8). Parallel to the setting of standards for practice has been the
building of this content into nursing curricula that have included developing
faculty expertise (9,10), assessing curricula (7,11,12), designing curricula
focusing on substance-related content in general (13–17), integrating evidence-
based screening and brief interventions in curricula (18,19), offering continuing
education (20), and participating in interdisciplinary faculty development
initiatives (9,21–23). Disciplinary and interdisciplinary faculty development
initiatives promoted expertise and enhanced curricula related to the full spectrum
of substance use, including prevention, detection, and treatment, a shift from the
focus primarily on treatment of these as disorders. This focus on the entire
continuum of substance use is consistent with mounting evidence of the
importance of prevention and early intervention emphasized by the World Health
Organization (WHO), which identified alcohol as the third leading cause of
preventable death globally (24). The NIAAA also promotes this wider view for
addressing alcohol use with the publication of practice guides for clinicians (25).
Thus, the global focus of addiction care has shifted to a broader upstream
approach aimed at reducing harm through prevention of at-risk substance use
and early intervention for those at risk for developing substance use disorders,
decriminalization of substance use, and broader policy initiatives (24,26,27).
This expanded view has required that nurses at all levels of practice broaden
their skill set from treatment of substance use disorders to include screening for
substance use and further assessment when that use increases the risk for adverse
health outcomes. Unfortunately, recent surveys of substance use in nursing
curricula do not reflect this shift to a broader approach to the problem of
substance use disorders. Mollica et al. (28) found little change in alcohol
curricular content from studies conducted more than 20 years ago. Survey
questions in most of the recent studies (28–30) continue to reflect the narrow
downstream focus on alcohol use disorder and treatment. Therefore, such studies
would be unlikely to capture information about substance use across the life
span, prevention strategies, and screening for at-risk use. Savage et al. (31)
conducted a national study of curricula in baccalaureate schools of nursing using
questions that reflected the broader scope of alcohol-related content, an essential
content as determined by an expert panel convened by the NIAAA (32). This
comprehensive survey included content on genetics, neurobiology of alcohol
addiction, prevention of alcohol use disorders, screening and brief intervention
(BI) for at-risk alcohol use and alcohol disorders, withdrawal management,
treatment for alcohol use disorders, alcohol-related health consequences, and
legal/ethical issues. Questions were designed to capture these content areas in
courses that addressed the life span and domains of nursing practice.
Comparison of findings from this study with the seminal 1987 study by Hoffman
and Heinemann revealed little progress over the last 24 years. Sixty-nine percent
of the schools in the new study reported 10 or less alcohol-related content hours
in the curriculum compared to 67% in the original study. Most of the content still
resided in the psychiatric/mental health courses, indicating that other important
areas are not addressed.
CURRENT TRENDS IN SUBSTANCE USE

Emerging trends in at-risk substance use have serious implications for nursing
practice, underlining the importance of developing a nursing workforce with the
knowledge and skills to actively participate in the prevention of adverse
consequences related to at-risk use as well as treatment of those with a substance
use disorder. There is increased recognition of and focus on the global burden of
substance use. For example, over 200 diseases and injuries are associated with
alcohol use (24). In the United States, 71% of all adults reported current alcohol
use in the past year with almost 60% reporting use in the past month (33). In
comparison, only 16.8% of adults reported tobacco use (34). Alcohol use and
tobacco use are among the well-known modifiable risk factors that contribute to
cardiovascular diseases, chronic respiratory diseases, cancers, and diabetes (35).
Of concern is the dramatic increase in substance use levels among older adults.
The Substance Abuse and Mental Health Services Administration (SAMHSA)
projects the need for addiction treatment among Americans over age 50 to
double by 2020. The most recent National Survey on Drug Use and Health
shows that about 4.3 million adults aged 50 or older used an illicit drug in the
past year. While marijuana was more common among men in that age group,
among those aged 65 and older, nonmedical use of prescription drugs was more
common than marijuana (36).
In addition to the serious health risks associated with alcohol and tobacco
use, the current scope of the opioid epidemic has raised alarm worldwide. Opioid
overdose deaths can result from a person taking an amount higher than the
prescribed opioid, taking opioid medication prescribed to someone else, or using
heroin or some other opioid. Globally, between 13 million and 21 million
persons aged 15 to 64 years use opioid, particularly heroin (37). In 2013, 4.5
million Americans age12 years and older reported using pain relievers in the past
month with 492 000 reporting OxyContin use in the past month (38). Spurred by
President Obama and the Office of National Drug Control Policy, various
national, state, and local initiatives have been aimed at supporting and expanding
community-based efforts to prevent drug use, pursuing approaches to drug
enforcement, improving prescribing practices for pain medication, increasing
access to treatment, working to reduce overdose deaths, and supporting the
millions of Americans in recovery. A number of professional nursing
organizations (eg, American Nurses Association; American Association of Nurse
Practitioners; American Association of Nurse Anesthetists; Association of
Women’s Health, Obstetric and Neonatal Nurses; American Psychiatric Nurses
Association; American Association of Colleges of Nursing; National Association
of Clinical Nurse Specialists; Nurse Practitioner Healthcare Foundation) have
pledged to be part of the solution in reversing the opioid epidemic (39).
A long-awaited change for which nurses have been outspoken is the need for
expanded access to treatment for persons with opioid use disorders (40). On July
22, 2016, President Obama signed into law the Comprehensive Addiction and
Recovery Act (CARA; P.L. 114-198). This legislation is a step toward expanded
access for persons needing treatment for an opioid use disorder. Section 303 of
this public law focuses on medication assisted treatment for recovery from
addiction. Language is included to allow nurse practitioners (NPs) and physician
assistants to “provide… all drugs approved by the Food and Drug
Administration for the treatment of opioid use disorder, including for
maintenance, detoxification, overdose reversal, and relapse prevention.”
Legislation is pending that will grant and extend buprenorphine prescribing to
the three other advance practice nurse roles (Clinical Nurse Specialist, Certified
Nurse Midwife, Certified Registered Nurse Anesthetist) which were not included
in CARA.
Effective reduction in the burden of disease associated with substance use
requires the ability to screen for alcohol and drug use across the life span and
conduct further assessment related to the amount and pattern of substance use as
well as any consequences associated with the use of alcohol, tobacco, and other
drugs. The comprehensive nursing role in addressing the full continuum of
substance use is evolving as the field is advancing. Since 2013, with funding
from the SAMHSA, there has been an increase in the number of model nursing
curricula integrating substance use–related content. Exemplars include curricula
for prelicensure students (18,19) and advanced practice nurses (41). Easily
accessible online educational programs are also being developed for nurses who
did not have this content in their academic program, such as one focusing on
alcohol screening and brief intervention for nurses (42). These educational
programs are designed to ensure that the future and current nursing workforce
has the requisite knowledge and competencies to provide evidence-based
interventions across the continuum of use and the life span for all levels of
practice and all practice settings.
LEVELS OF NURSING EDUCATION AND

PRACTICE
In 2008, the Robert Wood Johnson Foundation (RWJF) and the Institute of
Medicine (IOM) engaged in an initiative to assess and recommend changes in
the nursing profession. Data gathered for the IOM report revealed the following
information about nursing education and practice (43). Most nurses are RNs who
receive an associate degree (ADN) in a 2-year program at a community college
or a baccalaureate degree (BSN) in a 4-year university. Graduates of both levels
of nursing education are required to pass the same nationally standardized
licensing examination in the state where they intend to practice. Nurses with
ADN preparation typically provide direct patient care in various healthcare
settings. BSN nursing education includes additional preparation in leadership,
research utilization, and population health. Master’s degrees in nursing (MSN)
prepare nurses for administration, clinical leadership, faculty positions, or
advanced practice in a specialty area. Advanced practice registered nurse
(APRN) roles include the NP, the clinical nurse specialist (CNS), the certified
nurse anesthetist (CRNA), and the certified nurse midwife (CNM).
The NP is prepared to obtain histories and conduct physicals, diagnose and
treat illnesses, prescribe medications, order and interpret x-rays and lab tests, and
provide patient education and counseling (2). The scope of practice for NPs is
regulated by individual states, and there is a wide variation in limitations
imposed by the states. At present, 21 states and the District of Columbia have
approved full practice, that is, a provision that allows the NP to assess, diagnose,
interpret diagnostic tests, and prescribe medications independently (44). The
CNS provides advanced care in hospitals and other clinical sites, develops
quality improvement programs, and serves as educator and consultant. CRNAs
safely administer anesthesia in a variety of settings. A 2016 practice survey
report conveyed that CRNAs administer approximately 43 million anesthetics to
patients each year in the United States (45). CNMs provide primary care to
women including gynecology, family planning, prenatal care, low-risk labor and
delivery, and neonatal care (46).
Doctoral programs in nursing fall into two principal types: research focused
and practice focused. Most research-focused programs grant the doctor of
philosophy degree (PhD), while a small percentage offer the doctor of nursing
science degree (DNS, DSN, or DNSc) (47). These doctorally prepared nurses
develop the science, steward the profession, educate the next generation of
nurses, define its uniqueness, and maintain its professional integrity (47). The
practice-focused doctoral degree is the doctor of nursing practice (DNP), which
builds upon generalist education acquired through a baccalaureate or advanced
generalist master’s in nursing. DNP graduates are prepared for advanced practice
roles and leadership in clinical settings. The IOM report, The Future of Nursing:
Leading Change, Advancing Health (43), also sets forth recommendations to
prepare the nursing profession to be a part of the transformation of the healthcare
system. The report formulated the following key messages:
1. Nurses should practice to the full extent of their education and training.
2. Nurses should achieve higher levels of education and training through an
improved education.
3. Nurses should be full partners, with physicians and other health
professional, in redesigning health care in the United States.
4. Effective workforce planning and policy making require better data
collection and an improved information infrastructure.
The IOM report has profoundly impacted all levels of the profession. Nurse
educators are seeking to accommodate seamless academic progression to higher
levels of education, and nursing groups advocate for broader scope of practice
regulations for NPs. The lack of sufficient education in past and present nursing
curricula means that the current and future nursing workforce is not fully
equipped to address the nation’s alcohol and drug crises. Nurses specializing in
substance use and substance use disorder are critically needed to lead change and
advance the health of individuals, families, and populations affected by alcohol,
tobacco, and other drugs as well as maladaptive behaviors that may lead to
substance use disorder (48).
GENERALIST’S ROLES RELATED TO

ADDICTION
Considering the pervasive nature of at-risk substance use and substance use
disorders and the associated serious health consequences, it is imperative that
nurses at all educational levels have basic competencies to address this
phenomenon (49). Core competencies for the generalist nurse graduate related to
substance use were last identified in 2002 as a component of discipline-specific
recommendations outlined in the Strategic Plan for Interdisciplinary Faculty
Development (49). The Strategic Plan was a product of a 5-year collaborative
agreement between the Health Resources and Services Administration (HRSA)
and the Association for Medical Education and Research in Substance Abuse
(AMERSA) in collaboration with the Center for Substance Abuse Treatment
(CSAT) of the SAMHSA. The Strategic Plan was created to inform the federal
government and others how to improve alcohol and other drug education for
generalist health professionals (49). The document was also used as part of a
national initiative to train interdisciplinary faculty to enhance the curricula of
their respective disciplines to prepare their students to meet the challenge of
substance use (49). The disciplines included allied health, medicine, social work,
nursing, pharmacy, public health, psychology, physician assistants, and dentistry.
Competencies were recommended for each discipline by a panel of experts.
The core competencies as outlined by Naegle (4) for the generalist nurse can
be broadened across levels of practice and grouped under stages of the nursing
process. The nursing process is the basic sequence of steps used to define
nursing care. Stages of the nursing process include assessment, or data
collection; nursing diagnosis; desired measurable outcomes; nursing
interventions; and evaluation. Table 35-1 depicts core competencies considered
minimum knowledge and skills for generalist nurses educated at basic and
graduate levels for each stage of the nursing process as they relate to prevention
and treatment of substance use disorders. Two competencies also address
personal attitudes and values related to substance use.
TABLE 35-1 Nursing Substance Use–Related

Competencies
Adapted from Naegle MA. Nursing education in the prevention and treatment of SUD. Subst Abuse.
2002;23(Suppl 1):247-261.
Since the development of these competencies in 2002, significant changes in the
field of substance use have emerged and have impacted nursing. In addition to
the emerging trends previously discussed, evidence-based treatments including
pharmacotherapy are available.
The Comprehensive Addiction and Recovery Act (P.L. 114-198) expanded
the prescribing of buprenorphine to NPs. Nurses at all levels continued to have
key roles at all levels continue to have key roles in interdisciplinary teams and
settings where this medication is a key component of treatment. RNs continue to
have a critically important role in the management of patients on buprenorphine,
including conducting screening, assessment, treatment monitoring, counseling,
and supporting services and promoting relapse prevention skills (40,50,51). The
vital nature of these nursing activities is highlighted in the description of a
collaborative care office-based opioid treatment program wherein the nurse
program coordinator and RN case managers provided care along the continuum.
In this model, nurses demonstrated that they reduced the physician burden
through communicating and collaborating with prescribing physicians, addiction
counselors, and pharmacists (52). The value-added role of the nurse was
identified in another model of care integrating buprenorphine treatment into HIV
care with the point that “a nurse in the coordinator position gave the role and the
service the credibility, from the perspective of both patients and other providers”
(53). Thus, nurses can effectively provide high-quality care to the full extent of
their license and within the federal regulations for buprenorphine treatment.
Advances in neuroscience have informed the understanding of substance use
disorders as brain-based disorders, shifting from a moral view to a science-based
perspective. This paradigm shift can help diminish the blame and shame that is
the stigma associated with addiction and hopefully remove barriers to available
lifesaving treatments. With sufficient knowledge and competence, nurses can (a)
identify those at risk; (b) conduct further assessment; and based on the
assessment, (c) provide evidence-based interventions and, if within their scope
of practice, prescribe evidence-based medications to support abstinence and
recovery; and (d) ensure continuing care through referral to treatment (RT) for
those needing specialty treatment. Additionally, nurses across all settings and
specialties can teach patients and colleagues alike about the biological
mechanisms underlying substance use and how behavioral and pharmacological
treatments promote abstinence and recovery. Finally, the shift in the global focus
from treatment of substance use disorders to a focus on reducing harm related to
the continuum of use changes how nursing approaches competencies and the
leveling of those competencies across levels of practice. The stated
competencies are broad categories of requisite knowledge and skills for
generalist practice, which should be continually updated to reflect emerging
evidence in the field.
Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an
example of a set of practice strategies that should be provided by all generalist
nurses. Screening determines the extent of the substance use and signals the need
for additional assessment and interventions as indicated. BI is a
nonconfrontational, patient-centered approach to addressing unhealthy alcohol
and tobacco use and illicit drug use. BI is intended to raise awareness of the
consequences related to the substance use and motivate a patient toward
behavior change (ie, reduction in or cession of use). RT provides those patients
who need more extensive substance-related treatment with referral to specialty
care. An evidence-based practice for detecting risk, as well as substance use
disorder, and initiating appropriate clinician response, SBIRT has emerged as a
valuable tool. SBIRT has been shown to be effective in primary care patients
with nondependent alcohol use (54) but to have limited effectiveness for drug
use (55). Studies of SBIRT in emergency departments have found short-term
effectiveness for reducing risky alcohol consumption (56). Despite lack of
conclusive evidence about the effectiveness of SBIRT in various settings, in
2012, The Joint Commission (TJC) put forward four optional performance
measures related to tobacco and alcohol screening for hospitalized patients (57).
Nurse scientists have increasingly contributed to the body of science related
to SBIRT. Building on early work related to delivery of SBIRT by nurses in the
emergency department, Lauren Broyles conducted research examining nurse-
delivered SBIRT in hospitalized patients. In her cross-sectional study of 370
patients hospitalized in medical and surgical units, she found that patient
acceptability of nurse-delivered SBIRT was high (58), an important finding
considering the TJC measures for hospital accreditation (57). Other nurse
scientists have tested technology-based SBIRT interventions among patient
populations that may be particularly challenging to engage in treatment. Carol
Rose Dawson and colleagues tested an interactive, Web-based SBIRT
intervention embedded in the electronic record of patients at an urban, safety net
HIV primary care clinic (59). While feasible, the intervention may require
modifications for use in the study setting based on the finding that the
intervention was underutilized. Michael Sanchez is promoting universal
screening, BI and RT in HIV clinic settings, and providing guidance to nurses
(60). Amanda Choflet implemented SBIRT in an oncology setting with the goal
of improving both cancer-specific and all-cause patient outcomes (61). While
these are relatively new areas of investigation by nurse scientists, previous
studies have evaluated patient outcomes in which nurses delivered interventions.
A recent systematic review and meta-regression analyses analyzed data on
alcohol-related outcomes following delivery of an intervention by counselors,
general practitioners, nurses, peers, and others (62). The interventions delivered
by nurses had the most effect in reducing quantity but not frequency of alcohol
consumption (62). Thus, nurses have an impactful role in delivering various
types of alcohol interventions (ie, brief advice interventions, motivational
interviewing, enhanced motivational interviewing) in settings (ie, emergency,
community-based, primary care/ambulatory, inpatient/hospital) where they are
employed.
THE ADDICTION NURSE

While all RNs should have the requisite knowledge and skills outlined for the
generalist, there is a need for addiction nurses, specialists with advanced
knowledge and competencies related to substance use and substance use
disorder. The Scope and Standards of Addictions Nursing Practice reflects the
continuum of substance use and substance use disorders emphasizing the need
for prevention and treatment across all settings and specialties. The document,
prepared under the auspices of the International Nurses Society on Addictions
(IntNSA) and the ANA, sets forth the expectations of the professional role of
nurses who specialize in addiction. Per the Scope and Standards, this “role
commands knowledge of the fundamental biological, behavioral, environmental,
psychological, social, cultural, and spiritual aspects of human responses to the
use of substances and engagement in behaviors that can lead to addictive
disorders” (63). The standards coincide with the usual steps of the nursing
process and are intended to be applied to individuals, families, communities,
and/or populations. The standards of practice include assessment, diagnosis,
outcome identification, planning, implementation (encompassing coordination of
care, health teaching and health promotion, consultation, prescriptive authority,
and treatment), and evaluation. Standards of Professional Performance relate to
ethics, education, evidence-based practice and research, quality of practice,
communication, leadership, collaboration, professional practice evaluation,
resource utilization, and environmental health. Specific competencies for each
standard are identified for the RN specializing in addiction and the advanced
practice or graduate-level addiction nurse (63).
Through the Addictions Nursing Certification Board (ANCB), IntNSA has
taken the lead in providing certification for the specialty. The highest standards
of addiction practice are reflected by the Certified Addictions Registered Nurse
(64) and the graduate-level certification (CARN-AP) (65). CARN eligibility
requirements include current RN licensure with a minimum of 2000 hours of
nursing experience related to addiction as an RN and 30 hours of continuing
education related to addiction nursing within the previous 3 years. The number
of nurses holding the CARN as of November 2016 was 780. CARN-AP
requirements include a current RN license and a master’s degree or higher in
nursing. Applicants for the CARN-AP must have a minimum of 500 hours of
supervised, direct client contact in advanced clinical practice working with
individuals and families impacted by addiction and/or dual diagnoses; all 500
hours may be earned while in the master’s program. The number of nurses
holding the CARN-AP as of November 2016 was 176. The core curriculum for
addiction nursing is a primary source for nurses preparing to take these
examinations (66).
ADDICTION NURSING WORKFORCE

The CARN and CARN-AP certification examinations were informed by a Role
Delineation Study of the Addictions Nurse (67). The study was designed
specifically to describe the role and functions of nurses holding the CARN and
CARN-AP and their demographics, including employment settings and
educational background. A total of 1,027 invitations to participate in the study
were sent with 924 responding, 221 who indicated that they were practicing in
addiction nursing. Responses to the question about educational level indicated
that 38.6% were BSNs, 32.9% were ADNs, and 7.6% had been prepared in a
diploma or hospital-based program. At the graduate level, 13.9% held master’s
degrees, and 1.35% had doctoral degrees. The largest number of respondents
(43%) indicated that they worked in hospitals, while 34.2% worked in treatment
centers; 4.4% were engaged in private practice; 2.5% worked in schools; and
1.9% were in primary care. The majority of RN survey respondents (82%)
worked full time, and 75% functioned exclusively as addiction nurses. RNs
indicated that they spent the majority of their time providing patient care. APRN
survey respondents also indicated that they spent most of their time providing
direct patient care as clinical nurses, NPs, or consultants. Forty-nine percent of
the APRNs reported that they had prescriptive authority. The final count of 126
tasks and 43 knowledge statements endorsed by the respondents was then used
to compile content for the certification examinations. The results of this survey
provide a glimpse of the addiction nursing workforce and suggest the complex
nature of the practice by enumerating the tasks and requisite knowledge.
Specialty professional organizations for nurses engaged in addiction nursing
practice include the IntNSA. IntNSA was founded in 1975 as a component of the
National Council on Alcoholism. Mergers with the Drug and Alcohol Nurses
Association and the Consolidated Association of Nurses in Substance Abuse,
and the intent to become a global leader in the field, led to the organization’s
name change from the National Nurses Society on Addictions to IntNSA in
2000. The stated mission of the organization is “to advance excellence in nursing
care for the prevention and treatment of addictions for diverse populations across
all practice settings through advocacy, collaboration, education, research and
policy development” (68). IntNSA has a membership of approximately 850
nurses. In addition to sponsoring the certification examinations, IntNSA holds an
annual international education conference. The official journal of IntNSA is the
Journal of Addictions Nursing, an international peer-reviewed quarterly
publication. A feature of the journal includes interviews with addiction nurses
who are engaged in innovative roles. The nurses describe their roles as addiction
specialists and the paths they took to prepare for those roles. IntNSA also
publishes the Core Curriculum of Addiction Nursing, a comprehensive overview
of the specialty intended for clinicians, educators, and researchers, and, in
conjunction with ANA, the Scope and Standards of Addictions Nursing Practice.
As substance use–related knowledge and competency have been increasingly
sought after by nurses, special interest groups are emerging and growing. For
example, the Addictions Council of the American Psychiatric Nurses
Association advocates comprehensive, evidence-based interventions for
substance use and substance use disorder that are patient centered, population
focused, and delivered in a continuum of care, from prevention to recovery.
Since its inauguration in 1997, the Expert Panel on Psychiatric, Mental Health
and Substance Abuse has undertaken policy-related initiatives to improve the
public’s mental health and the delivery of high-quality mental/behavioral health
care and to inform policy makers about nursing’s contributions to
mental/behavioral health care. One such policy publication relates to removing
barriers to increase the use of SBIRT for reducing the risks associated with
alcohol (69).
Nursing roles in addressing at-risk substance use and the prevention and
treatment of substance use disorders have expanded over the past two decades as
more is known about the phenomenon of substance use. Standards of care and
accrediting bodies have embraced the concept of universal screening for at-risk
alcohol use by all healthcare providers (67). In addition, there is a better
understanding of the impact substance use has on the burden of disease (35). The
knowledge and competency needed by nurses at all levels of expertise
(generalist and specialist) include multiple components of care, screening,
assessment, interventions, and referral for treatment. Current screening
guidelines help nurses to identify those at risk for harm related to substance use
as well as provide a process for delivering interventions aimed at reduction of
the harm associated with a patient’s substance use. An area that is beginning to
receive more attention is the incorporation of substance use into the nursing
assessment of the relationship of current use to the health status of the patient.
For example, assessment of the quantity, frequency, pattern, and duration of use
provides important information related to possible drug interactions. The
challenge is to keep pace with these changes through education to prepare all
nurses to respond to the full spectrum of substance use, from prevention of at-
risk use to treatment of substance use disorders, across the life span.
In conjunction with developing the knowledge and skills of all nurses across
all healthcare settings and specialty areas is the need to build the nursing
workforce in the specialty of addiction nursing. To meet the demands across the
spectrum of care related to substance use, the need for nurses certified at the
generalist or advanced practice level in addiction nursing is growing. For
example, to meet the American College of Surgeons and TJC standards,
hospitals need nurses with the specialty background to implement and evaluate
these programs and provide the needed training. Nurses are acquiring a stronger
voice in the field of addiction at the state and national level through the
leadership of addiction nursing. To strengthen this voice, developing educational
programs at the advanced practice level in schools of nursing should be a
priority.
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CHAPTER 36
International Perspectives on Addiction
Management*
Nady el-Guebaly, Vladimir Poznyak, and Gilberto Gerra
CHAPTER OUTLINE
Introduction
Worldwide Prevalence of Psychoactive Substance Use and Substance Use
Disorders
International Policy Frameworks for Psychoactive Substances
The Role of the World Health Organization and United Nations Office on
Drugs and Crime
The Evolving Role of International Medical Associations
Conclusions
INTRODUCTION
International efforts to reduce the health and social burden attributable to
psychoactive substance use are gaining momentum, and in recent years, there is
a clear trend toward putting more emphasis on public health measures, including
prevention and treatment of substance use disorders (SUDs), which are the
cornerstones of addiction medicine. This chapter will focus on major
international endeavors: the first section, on relevant global data largely coming
out from the United Nations (UN) system, and the subsequent two sections, on
the international policy frameworks for psychoactive substances and the role of
the UN system, including World Health Organization (WHO) and the United
Nations Office on Drugs and Crime (UNODC). The third part describes the
mostly volunteer efforts of physicians to develop international networks to
address the public health aspects of the use of drugs. These collaborations have
resulted in a number of international medical organizations committed to
demand reduction, including the World Medical Association, the World
Psychiatric Association (WPA), and the International Society of Addiction
Medicine (ISAM).
WORLDWIDE PREVALENCE OF
PSYCHOACTIVE SUBSTANCE USE AND
SUBSTANCE USE DISORDERS
Worldwide psychoactive substance use is highly prevalent, and large segments
of the world population are exposed to the effects of dependence-producing
(a.k.a. “addictive”) substances. Alcohol is the most widely used psychoactive
substance worldwide, and about 2.6 billion people use alcohol beverages around
the world or ~52% of the world’s adult population (1). Currently, more than 1
billion people in the world, or 21% of the world’s adult population (aged 15
years and over), are estimated to be tobacco smokers (2), and around 247 million
people, or 5% of the world’s adult population, are estimated to have used other
psychoactive drugs at least once in 2014 (3). A significant proportion of people
who repeatedly use substances such as alcohol, tobacco, or other drugs develop
SUDs. According to the WHO estimates, in 2010, the number of people with
DSM-IV-TR–defined alcohol dependence or harmful use of alcohol worldwide
reached 283 million (1), with differences across the world’s regions (Fig. 36-1).
Figure 36-1 Prevalence (%) of alcohol use disorders

(AUDs*) by sex, WHO region and the world, 2010 (WHO,
2014). *The prevalence of AUDs is the sum of the
prevalence of harmful use and alcohol dependence, in line
with ICD-10 criteria (WHO, 1992). AFR, African Region;
AMR, Region of the Americas; EMR, Eastern Mediterranean
Region; EUR; European Region; SEAR, South East Asia
Region; WPR, Western Pacific Region.
In 2014, according to UNODC estimates, the number of people with drug use
disorders was 29 million (3). The UNODC’s World Drug Report 2016 estimates
the total number of individuals using drugs as 247 million people. Cannabis
represents the first and amphetamine-type stimulants, or ATS, the second most
widely used classes of substances, followed by “ecstasy,” opioids, and cocaine.
Estimated number of people aged 15-64 years who used illicit drugs at least once
in the past year is presented in Table 36-1.
TABLE 36-1 Estimate of Past Year Use
Estimated number of people aged 15 to 64 years who used illicit drugs at least once in the past year
(UNODC, 2016).
UNODC estimates indicate that 29 million people, equivalent to 0.6% of the

world population aged 15-64, suffer from drug use disorders (3). The 2016
report provided an overview of trends in consumption of the main types of these
psychoactive drugs from 2006 to 2013. The available information suggests that
the use of synthetic substances and the nonmedical use of prescription opioids,
tranquilizers, and prescription stimulants are increasing. Cannabis use is
increasing in North America, Africa, and Asia, while ATS use is increasing in
Asia and Africa. In contrast, the consumption of heroin and cocaine is stabilizing
or decreasing, even in high-consumption countries (cocaine in North America
and heroin in Western and Central Europe).
The public health impact and burden of psychoactive substance use are not
limited to SUDs, and significant harm comes from acute intoxication, risks
associated with the form of administration, or toxic effects of a substance (4).
According to the WHO estimates for 2012, about 3.3 million deaths, or 5.9% of
all global deaths, were attributable to alcohol consumption (1), and a major
portion of these deaths are not resulting from alcohol use disorder per se. These
data have important policy implications: from a public health perspective,
effective reduction of the disease burden attributable to alcohol cannot be
achieved just by treatment of alcohol use disorder and implies a broader
spectrum of effective policies.
UNODC estimates for 2014 indicate more than 200,000 drug-related deaths,
at least a third of which are attributable to overdose, mostly of opioids, and are
thus preventable (3).
In the last 30 years, one of the most visible consequences of drug use
disorders has been human immunodeficiency virus infection and acquired
immunodeficiency syndrome (HIV/AIDS), and it is estimated that more than
10% of all HIV infections worldwide are due to the use of contaminated drug-
injecting equipment. Data indicate that there are 12 million persons who inject
drugs worldwide (3). It also indicates that sharing of contaminated injection
equipment is a major route of HIV transmission in many regions, including
Eastern Europe; Central, South, and South East Asia; and some countries in
Latin America (5).
Hepatitis C virus infection is emerging as a global public health challenge
that affects disproportionally injecting drug users. According to the recent
systematic review and meta-analysis supported by WHO, in HIV-infected
individuals who inject drugs, HIV–HCV coinfection is estimated at 82.4% (55.2-
88.5) in comparison with 2.4% (0.8-5.8) within general population samples.
Worldwide, from ~2.3 million HIV–HCV coinfections, 1.4 million are in people
who inject drugs (PWID) (6).
INTERNATIONAL POLICY
FRAMEWORKS FOR PSYCHOACTIVE
SUBSTANCES
All current international policy frameworks for psychoactive substance were
negotiated and concluded under the auspices of the UN. The international drug
treaties have the longest history dating back to 1912, and the present framework
of the international drug control system is based on three conventions: Single
Convention on Narcotic Drugs of 1961 (as amended by the 1972 Protocol),
Convention on Psychotropic Substances of 1971, and the United Nations
Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances
of 1988 (7). The conventions provide the international legal basis for regulating
the supply of and the demand for a wide range of psychoactive drugs with a
view to ensuring their availability for medical and scientific purposes only. The
three major international drug control treaties are complementary and aim at
reducing human suffering and protecting the public health and welfare by
ensuring the availability of controlled medicines (such as opioid analgesics,
benzodiazepines, and stimulants) for medical and scientific purposes while
reducing their nonmedical use. Particularly relevant to addiction medicine, the
conventions specify that signatory countries take all practicable measures for the
prevention of “abuse” of drugs (terminology used in the conventions) and for the
early identification, treatment, education, aftercare, rehabilitation, and social
reintegration of the persons involved. They also require parties to promote the
training of personnel involved in delivering such interventions and to facilitate
an understanding of the problems of unhealthy drug use among professionals
and the general public. The conventions further state that when individuals who
use drugs have committed drug offenses, countries may provide drug treatment,
education, aftercare, rehabilitation, and social reintegration either as an
alternative or as an addition to conviction or punishment. Such bridges between
the criminal justice system and the treatment system may be established at
different stages of the criminal process, including the prosecution stage or at the
stage of enforcement of a prison sentence (7).
The International Narcotics Control Board (INCB) had already
acknowledged the importance of certain aspects of “harm reduction” in 1993 (8),
while noting that they should not become a substitute for drug prevention and
treatment. In its 2003 report, the Board further noted that “Governments needed
to adopt measures that may decrease the sharing of hypodermic needles among
PWID in order to limit the spread of HIV/AIDS” and observed that “many
Governments have opted in favor of drug substitution and maintenance
treatment” and that “the implementation of this treatment does not constitute any
breach of treaty provisions, whatever substance may be used for such treatment
in line with established national sound medical practice” (9).
The most recent international treaty for psychoactive substances, the WHO
Framework Convention on Tobacco Control (WHO FCTC), was negotiated
under the auspices of the WHO in 2003 and entered into force in 2005 (10). The
WHO FCTC has been signed and ratified by some 180 countries to date.
However, while the United States helped to inspire the concepts of the treaty and
signed it, the United States has not yet ratified the treaty and is not a full party to
the treaty whose stated objective is “to protect present and future generations
from the devastating health, social, environmental and economic consequences
of tobacco consumption and exposure to tobacco smoke” (10). Though most of
the articles of the WHO FCTC are concentrated on population-based prevention
measures such as tax increases, bans on advertising, and protection from
exposure to tobacco smoke in indoor public places, Article 17 of the convention
addresses the measures directly supporting prevention and treatment of nicotine
use disorder, including counseling, psychological support, nicotine replacement
therapy, and education programs. Parties are required to develop and disseminate
national guidelines on tobacco use disorder treatment and are encouraged to
establish sustainable infrastructure for such services. Guidelines for
implementation of these measures specify a broad range of actions that are
recommended to support tobacco cessation and treatment of tobacco dependence
including provisions for availability and affordability of effective medications
and establishing a network of specialized treatment services for treating tobacco
dependence that meet national or applicable standards of care (11).
Alcohol is the only commonly used worldwide psychoactive substance with
significant potential for unhealthy use that is currently not covered by legally
binding international treaty. As an alternative, the global nonbinding policy
framework—global strategy to reduce the harmful use of alcohol—was
negotiated by WHO Member States and endorsed by the World Health Assembly
in 2010. The strategy presents as one of its guiding principles that individuals
and families affected by the harmful use of alcohol should have access to
affordable and effective prevention and care services, and health services’
response is one of ten key policy areas for implementing the strategy at national
level. The strategy specifies further policy options and interventions for this
area, which include, inter alia, increasing capacity of health and social welfare
systems to deliver prevention, treatment, and care for alcohol use and alcohol-
induced disorders and comorbid conditions, including support and treatment for
affected families; supporting initiatives for screening and brief interventions for
hazardous and harmful drinking at primary healthcare and other settings; early
identification and management of harmful drinking among pregnant women and
women of childbearing age; improving capacity for prevention of, identification
of, and interventions for individuals and families living with fetal alcohol
spectrum disorders; and development and effective coordination of integrated
and/or linked prevention, treatment, and care strategies and services for alcohol
use disorders and comorbid conditions, including drug use disorders, depression,
suicides, HIV/AIDS, and tuberculosis (12).
Adoption of the 2030 Agenda for Sustainable Development (SDG 2030)
gave a new global support for the international and national efforts on prevention
and management of SUDs. Its health target 3.5 sets out a commitment by
governments to “strengthen the prevention and treatment of substance abuse,
including narcotic drugs and harmful use of alcohol” (13). The leading role in
supporting countries in achieving the SDG 2030 health target 3.5 belongs to the
WHO and UNODC.
With regard to psychoactive drugs, this important area of work was given
further impetus by the adoption in 2009 of the Political Declaration and Plan of
Action on International Cooperation toward an Integrated and Balanced Strategy
to Counter the World Drug Problem, which provide focus for the work of the UN
system in supporting Member States in achieving significant and measurable
results in the field of demand reduction by the year 2019 (14). In April 2016, the
United Nations General Assembly’s special session (UNGASS) reviewed the
progress made in the implementation of the Political Declaration and Plan of
Action with an assessment of the achievements made and challenges
encountered. In the adopted outcome document, which emphasizes the
importance of public health measures and protection of human rights in
countering the world drug problem, Heads of State and Government, ministers,
and representatives of Member States made operational recommendations on
demand reduction. These recommendations recognize drug use disorder as a
complex, multifactorial health disorder that can be prevented and treated through
evidence-based interventions and call for promoting and strengthening
international cooperation in developing and implementing prevention and
treatment-related initiatives to ensure nondiscriminatory access to a broad range
of evidence-based interventions by those in need. The outcome document
adopted by the UNGASS in 2016 signified an important shift in implementation
of drug control treaties from predominantly supply reduction measures toward
public health–oriented measures including prevention of drug use, as well as
treatment, rehabilitation, recovery, and social reintegration of people with drug
use disorders (15).
Overall, the international policy frameworks for psychoactive substance use
have a substantial impact on the context and nature of demand for treatment and
service provision in different jurisdictions, and health professionals, including
addiction medicine specialists, have an important role to play in supporting their
public health oriented implementation and further development.
THE ROLE OF THE WORLD HEALTH
ORGANIZATION AND UNITED NATIONS
OFFICE ON DRUGS AND CRIME
WHO is a directing and coordinating authority for health within the UN systems,
whereas the UNODC is the leading UN entity for countering the drug problem.
In response to the various mandates reflected under the international policy
frameworks for psychoactive substance use, the work on prevention and
management of substance use and SUDs is an integral part of the activities of
both WHO and UNODC.
UNODC-WHO Program on Drug Dependence Treatment and Care is built
upon complementary mandates, experience, competencies, and networks of
WHO and UNODC. It has the overall goal of promoting and supporting
worldwide, with a particular focus on low- and middle-income countries,
evidence-based and ethical treatment policies, and strategies and interventions to
reduce the health and social burden caused by drug use and drug use disorders.
Within this collaborative program, technical assistance in developing drug
treatment systems was provided to more than 20 low- or middle-income
countries. This collaboration resulted in development, publication, and
worldwide dissemination of several key publications of direct relevance to
addiction medicine, including discussion papers on principles of drug treatment
(16), opioid overdose prevention (17), and more recently International Standards
for the Treatment of Drug Use Disorders (18). The Standards define a set of
requirements that must be in place before any form of outreach, treatment,
rehabilitation, or recovery services may be considered safe and effective care.
Seven principles provided within the document are presented in Table 36-2.
TABLE 36-2 Principles of Drug Dependence Treatment

Key Principles of Drug Dependence Treatment (The International Standards for the Treatment of Drug Use
Disorders, draft version [UNODC and WHO, 2016]).
The UNODC and WHO publications on management of drug use disorders

emphasize that interventions and investments in treatment should be guided by
respect for human rights, evidence-based practices, and the high-quality
standards that are required to approve pharmacological or psychosocial
interventions for drug use disorders. “Nothing less than for any other medical
condition” is a motto that is being promoted by UNODC-WHO program on drug
dependence treatment and care. Community- and prison-based treatment and
rehabilitation programs can form part of the same overall treatment system and
guarantee the same level of quality. In an international context, such
interventions and strategies need to be adapted to the diverse regional, national,
and local circumstances, taking into account cultural and economic factors. More
recently, UNODC and WHO have actively collaborated on the interaction
between health and criminal justice systems with the aim to support treatment of
people with drug use disorders committing minor drug-related crimes as an
alternative to punishment and imprisonment, and a collection of good practices
is being developed. UNODC and WHO have also collaborated in initiatives
promoting evidence-based prevention, such as the ongoing campaign “Listen
First” (www.unodc.org/listenfirst), and the development of guidance on how to
address substance use in the context of the education sector in collaboration with
the United Nations Educational, Scientific and Cultural Organization, commonly
known as UNESCO.
UNODC also leads additional initiatives to support Member States in
improving their drug prevention and treatment systems. Following the
publication of guidelines on how to implement family-based prevention and a
compilation of evidence-based programs, UNODC has been supporting the
piloting of evidence-based family skills training programs in more than 20
countries worldwide. These skills training programs target the behavior of
children, parents, and families to strengthen protective factors and prevent
substance use and other risky behaviors such as violence. The programs also aim
to change attitudes of national stakeholders, particularly policymakers, with
regard to the importance of evidence-based interventions (19).
In a broader effort to promote a comprehensive approach to the prevention
of drug use and risky behaviors that is based on evidence and supports the
healthy and safe development of children and youth, UNODC undertook a
systematic review of the evidence on prevention that resulted in publication in
2013 as the International Standards of Drug Use Prevention (20) (Table 36-3).
TABLE 36-3 Evidence Based Interventions and Policies

Note: Strategy with an indication of efficacy (⋆limited/⋆⋆adequate/⋆⋆⋆good/⋆⋆⋆⋆very good/
⋆⋆⋆⋆⋆excellent). See above for a description of the information implied by this indication.
■ = Universal—strategy appropriate for the population at large.
■ = Selective—strategy appropriate for groups that are particularly at risk.
■ = Indicated—strategy appropriate for individuals that are particularly at risk.
Summary of Interventions and Policies Found to Yield Positive Results in Preventing Substance Use.
(Adapted from Campello G, Heikkila H, Maalouf W. International Standards on drug use prevention: tools
to support policy makers globally to implement an evidence-based prevention response. In: Israelashvili
M, Romano JL, eds. Cambridge Handbook of International Prevention Science. New York, NY:
Cambridge University Press, 2017.)
With regard to drug treatment and care, a large UNODC program supporting
Member States through guidance, training, and service improvement called
“Treatnet” has been subsumed under the UNODC-WHO program on drug
dependence treatment and care. Throughout its life, Treatnet has been active in
more than 40 countries and has published important resources for Member States
such as the Treatnet Training Package (21) and “From Coercion to Cohesion,”
the first UNODC publication focusing on promoting evidence-based treatment
that is voluntary, including as an alternative to criminal justice sanctions (22).
One of the core functions of WHO is to monitor the health situation and
assess health trends. A groundbreaking international effort to quantify the
disease burden of different diseases and health conditions was the influential
Global Burden of Disease (GBD) study. Mortality estimates and the estimates of
disease burden expressed in disability-adjusted life years (DALY) lost provided a
better understanding of the impact of psychoactive substance use on the
population health (23).
Regular updates of the initial estimates as well as the use of more outcomes
have been calculated (24). The GBDs and Injuries and Risk Factors study, 2010,
calculated the burden of illicit drug dependence separately for amphetamines,
cocaine, opioids, and cannabis (25). Illicit drug dependence directly accounted
for 0.8% (0.6-1.0) of global all-cause DALYs. Worldwide, more people were
dependent on opioid and amphetamine than other drugs (with opioid dependence
being the largest contributor) (26). Currently, the WHO has set up a Global
Information System on Alcohol and Health (GISAH) as the global information
and monitoring tool for collecting, compiling, analyzing, and disseminating data
for monitoring the global situation in the area of alcohol and health. According
to WHO estimates for 2012 presented in the latest WHO global status report on
alcohol and health (1), the prevalence of alcohol use disorders in the world
population of 15+ years old is 4.1% with the highest prevalence in the WHO
European region (7.5%) and Americas (6.0%). WHO also implements the
ATLAS-SU project that aims to monitor at the global level available resources
for prevention and treatment of SUDs (27).
Reducing tobacco use is one of the key objectives of the current WHO work
on the global tobacco epidemic supported by the WHO Framework Convention
on Tobacco Control (10). The WHO advocates for the six most effective tobacco
control policies: raising taxes and prices; banning advertising, promotion, and
sponsorship; protecting people from secondhand smoke; warning everyone about
the dangers of tobacco; offering help to people who want to quit; and carefully
monitoring the epidemic and prevention policies (2).
The WHO has, for many years, advocated for the promotion of screening
and brief intervention procedures for hazardous and harmful use of alcohol in
healthcare and other settings, which proved to be effective and cost-effective
(28). The WHO sponsored the Project on Identification and Management of
Alcohol-Related Problems in numerous countries with the objective of adoption
of screening and brief interventions in national or regional healthcare systems to
achieve the impact on population health (29). Applying the principles of Alcohol
Use Disorders Identification Test (AUDIT)-based screening and brief
interventions for alcohol problems, the WHO initiated and supported the
development of a screening instrument for hazardous and harmful use of any
psychoactive substance, from tobacco to heroin and cocaine, which resulted in
the development and testing of the WHO instrument called ASSIST (Alcohol,
Smoking, and Substance Involvement Screening Test) (30) followed by the study
of the effectiveness of brief interventions in reducing drug use among clients of
healthcare settings (31) and release of the manuals for screening and brief
interventions based on the ASSIST including the self-help manual (32–34).
Building up on the WHO report “Neuroscience of psychoactive substance
use and dependence,” WHO continues to promote the concept of substance
dependence as “a complex disorder with biological mechanisms affecting the
brain and its capacity to control substance use” (4), which is also reflected in the
ongoing WHO’s work on a new revision of the International Classification of
Diseases (ICD-11). Pharmacological interventions are important components of
public health interventions for SUDs, and a section “Medicines used in
substance dependence programs” is included in the WHO Model List of
Essential Medicines with methadone and buprenorphine as the first medications
included in this section (35).
In accordance with its core functions, WHO develops guidelines and other
technical tools to support health systems and programs in different countries on
prevention, identification, and management of health conditions leading to
increased mortality and disability in populations. In the area of addiction
medicine, WHO produced the guidelines on pharmacotherapy of opioid
dependence with a strong focus on methadone and buprenorphine (36), on
management of substance use in pregnancy (37), and on management of opioid
overdose focused on naloxone availability and administration (38), and
important drug-related recommendations are included in the guidelines on HIV
prevention and management (39). To promote identification and effective
management of mental, neurological, and SUDs in primary healthcare and other
nonspecialized settings, WHO developed the mhGAP Intervention Guide with a
section on SUDs and supported dissemination and implementation of this tool in
many countries (40).
Development of a treatment system for SUDs should be an integral part of
the overall response to health and social problems and an integral part of the
overall health and social welfare systems. With this approach, it is feasible to
achieve one of the key WHO objectives—the universal health coverage (UHC)
for people suffering from SUDs that implies (a) coverage for the entire
population, (b) the full spectrum of quality health services available according to
needs, and (c) financial protection from direct payment for health services when
consumed (41).
THE EVOLVING ROLE OF

INTERNATIONAL MEDICAL
ASSOCIATIONS
The founding of medical associations created opportunities for addressing issues
of global concern by medical professionals. The World Medical Association has
several position statements in relation to the use of substances
(http://www.wma.net/en/30publications/10policies/index.html) (42). After World
War II, the World Medical Association modernized the Hippocrates Oath in 1948
to what became known as the “Declaration of Geneva” enshrining an
International Code of Medical Ethics. Spurred by similar ethical concerns in
relation to the treatment of mental disorders, the WPA was founded in 1950. It
now includes two sections of addiction psychiatry and dual disorders that
organize educational activities about substance and behavioral addiction at
meetings of the WPA and provides an addiction perspective on international
strategies such as the development of a physician health and wellness
international network or the optimal psychiatric response to comorbidities. It
also contributes to the WPA role as a watchdog against the occurrence or
recurrence of abuses of those suffering from mental illness and addiction (43).
To address the international aspects of addiction medicine, the need for an
international society was recognized by international attendants at a number of
meetings of the American Society of Addiction Medicine (ASAM) since the
mid-1990s. On April 26, 1998, 25 physicians representing 11 countries from
four continents met in New Orleans and decided to formalize their international
collaboration. In 1999, at a founding meeting at the Betty Ford Center in Palm
Springs, the ISAM came into being. The ISAM committed itself to advancing
knowledge about addiction as a treatable disease, to advocating for the major
role worldwide of physicians in addiction management as well as enhancing the
credibility of their role, and, lastly, to developing educational activities including
consensus guidelines (44).
Eighteen years later, the ISAM has a membership spanning 73 countries
from six continents. It is a membership organization as well as a network of
regional and national societies representing countries such as Argentina,
Australia, Canada, Chile, Egypt, Finland, Iceland, Indonesia, Italy, Japan, Korea,
the Netherlands, Norway, Romania, Saudi Arabia, South Africa, Thailand, the
United Kingdom, and the United States. It has a special affiliation agreement
with the American, Austrian, Canadian, Dutch, Egyptian, Finnish, Icelandic,
Israeli, Japanese, Korean, Norwegian, and Swiss Addiction Medicine Societies.
Institutional affiliations are being developed as well. ISAM also welcomes
associate memberships from allied health disciplines; the only activity restricted
to physicians is board membership. Differential dues based on their economic
potential follow the four World Bank categories of countries. In 2015, a further
membership category of Fellowship was finalized; 49 members were granted
Fellowship status in 2016, having met eligibility criteria including long-standing
membership and significant service contributions to ISAM.
The Advocacy Role

The same objectives guiding the advocacy of the ASAM are at play in various
countries of the world. Embarking on a career in addiction medicine means
battling the public stigma attached to the disease that rubs off on the care
providers. By and large, the general attitudes of the medical profession mirror
those of the public. As the national organizations are involved in similar
struggles within different resource constraints, an umbrella international
organization can provide the external validation required to strengthen national
advocacy. For example, several national medical insurance schemes, such as
Canada’s, successfully provide parity coverage for the treatment of addiction
disorders, thus contributing to the validation required by the United States as it
strives for such parity.
International medical associations help bolster the perception of addiction as
a treatable disease by disseminating information about empirically based
treatment practices arising from various parts of the globe while respectful of the
local culture. This often involves a local needs assessment gathered by local
medical opinion leaders and a culturally sensitive stepwise approach to remedial
action. The ISAM has supported the research surrounding the experimental
application of the ASAM’s patient placement criteria in diverse systems of care
(45).
International Dissemination of Information
From the onset, a major goal for the ISAM was to hold an annual meeting in
different parts of the world to overcome the barriers of distance and travel costs
and network with practitioners worldwide. The ISAM has so far held or
cosponsored 21 meetings in 19 countries. Travel fellowships partly supported by
the WHO and the National Institute on Drug Abuse (NIDA) help reduce the
burden of cost. For members of the ISAM, the world becomes a much smaller
place, connections with colleagues from across the globe are established, their
programs and practices are directly observed, and the impact of their national
drug strategies is compared. At each meeting, the local organizing committee
strives to display their country’s reservoir of hospitality and ensure optimal
safety. The presentations are in English, but a half-day track may be allotted to
presentations in the local language. The meetings bring visibility to the field
locally and raise public awareness through media reports.
A number of complementary educational activities have also been
developed, including an information website (www.isamweb.org), a newsletter,
and several position papers (44). The ISAM members are also playing key roles
in the previously described UNODC Treatnet and the UNGASS feedback.
Recently, the ISAM sponsored a 4-volume reference work, Textbook of
Addiction Treatment: International Perspectives, Springer/Verlag: Italia, 2015,
reflecting the fact that addiction is increasingly recognized as a major global
public health issue. This textbook collates the experience and wisdom of 281
leaders in the field from 30 countries, contains 150 chapters in 12 sections, and
highlights the core knowledge of addiction medicine worldwide, as well as
serving as the basis for the ISAM Certification (46).
International Accreditation of Specialists

The development of a field with specialized expertise must be accompanied by
an accreditation process. Since 2005, an International Certification in Addiction
Medicine with an international editorial board has been held with applicants
from 15 countries and 119 certificants so far (44). Based on the ASAM’s
pioneering efforts, the International Certification strives to provide affordable,
valid, and comparable international credentialing. It is mainly a test of
knowledge with several clinical judgment questions. It is not meant to compete
with national qualifications but rather to be a main resource for countries that do
not have such a validation instrument and eventually establish an internationally
standardized core test of knowledge in addiction medicine. National legislation
and/or cultural requirements as well as observation of clinical skills could be
easily tagged to the core knowledge test. The criteria of eligibility of physicians
for writing the exam are meant to be inclusive. The certification test also helps
point “new knowledge” frontiers to be promoted in the educational activities.
Currently, knowledge about behavioral addiction as well as the management of
pain and addiction constitutes two such frontiers. Another challenge is for the
exam to be as “culturally neutral” as possible.
Reaching Out to Colleagues From Developing

Countries
Resource constraints are a major impediment to our colleagues in many areas of
the world. Aside from a differential fee structure, organizing meetings in
different continents, and maximizing our electronic outreach, the ISAM has
collaborated with the WHO and NIDA in providing fellowships to colleagues
from developing nations and young investigators (44).
Impact of Culture on Medical Practice

Policies addressing the use of various drugs including alcohol and nicotine vary
from country to country. The management of opioid use disorder may, arguably,
arouse the most polarizing divide among national drug policies and, more
specifically, the support or denial of the need for opioid agonist treatment.
Although significant progress is being made in areas of the world where the use
of opioids creates the heaviest burden of morbidity, cultural and structural
factors still impede the dissemination of opioid agonist treatment. The
international medical associations are striving to promote empirically based
practices that account for the local culture and economic resources. In many
Islamic countries, for example, a thriving network of therapeutic communities
with religious underpinning is the main resource for the management of opioid
use disorder. More recently, countries such as Iran and China have incorporated
methadone and/or buprenorphine treatment as part of their strategic panoply to
combat opioid use disorder (47).
Many countries limit their treatment efforts to opioid withdrawal
management. This preference has spurred the development of controversial
practices such as rapid antagonist induction under general anesthesia. The long-
term effect of the procedure is not supported by evidence (48). One of the goals
of international collaborations and structures is to reduce the use of ineffective
practices and policies as well as to promote evidence-based solutions.
CONCLUSIONS
While demand reduction policies have gained international momentum in recent
decades, increased political support and financial commitment are needed to
develop further effective and ethical policies and programs for prevention and
treatment of SUDs. Development of adequate international responses to
problems related to psychoactive substance use requires concerted action.
Collaborative synergy is emerging among the main international bodies involved
in the management of legal and illegal drug problems, such as the WHO and the
UNODC, research institutes such as the NIDA and the NIAAA in the United
States, and the medical associations, such as the ISAM, concerned with the
related problems. However, each organization has a need for further resources to
facilitate the necessary collaborations.
Prevention and treatment approaches delivered within the community and as
a continuum of care can maximize coverage and response to needs as well as
help reduce stigma and discrimination. International mechanisms for knowledge
transfer such as communities of knowledge, networks, and partnership schemes
are key to disseminate evidence-based practices and ultimately improve the
quality and effectiveness of interventions. Health professionals, and particularly
specialists in addiction medicine, have an important role in developing, shaping,
and implementing international responses. The medical associations have a
major peer-led educational role either through their meetings and fellowships or
in collaboration with other organizations’ activities. Standard curricula are being
developed. The associations promote culturally sensitive, empirically based
medical practices at the local level and help credential local medical
practitioners.
To achieve public health goals and impact on population health, it is
imperative to go beyond individual-level interventions and promote and support
effective problem- and population-based preventive strategies and measures on
an international basis.
ACKNOWLEDGMENTS
The contributions of Dr. Dzmitry Krupchanka (WHO) and Dr. Giovanna
Campello (UNODC) are hereby gratefully acknowledged.
Disclaimer: Dr Vladimir Poznyak, is a staff member of the World Health
Organization. The author alone is responsible for the views expressed in this
publication and they do not necessarily represent the decisions or policies of the
World Health Organization.
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Geneva, Switzerland: WHO, 2013.
42. World Medical Association: World Medical Association Statement on the Responsibilities of
Physicians in Preventing and Treating Opiate and Psychotropic Drug Abuse. Adopted by the 57th
General Assembly Pilanesberg, South Africa and revised by the WMA General Assembly, Taipei,
Taiwan, October 2016. Retrieved on January 12, 2016.
http://www.wma.net/en/30publications/10policies/a27/index.html
43. World Psychiatric Association. Retrieved on January 2017. http://www.wpanet.org/detail.php?
section_id=5&content_id=4
44. International Society of Addiction Medicine. ISAM Web page. Retrieved on December 13, 2016.
www.isamweb.org
45. Gastfriend DR, Mee-Lee D. Patient placement criteria. In: Galanter M, Kleber HD, eds. The
American Psychiatric Publishing Textbook Substance Abuse Treatment. 4th ed. Washington, DC:
American Psychiatric Publishing, 2010:99-123.
46. el-Guebaly N, Carra G, Galanter M. Textbook of Addiction Treatment: International Perspectives.
Italia: Springer/Verlag, 2015.
47. Zhao M. Implementation of methadone maintenance treatment in china. In: el-Guebaly N, Carra G,
Galanter M, eds. Textbook of Addiction Treatment: International Perspectives. Italia: Springer/Verlag,
2015:531-542.
48. Collins ED, Kleber HD, Whittington RA, et al. Anaesthesia-assisted versus buprenorphine-or
clonidine-assisted heroin detoxification and naltrexone inductions. A randomized trial. JAMA.
2005;294:903-913.

* In this chapter, we use the international nomenclature, which is slightly different from what is being used
in the United States. The WHO does not abandon the concept of dependence syndrome and this term will
continue to be present in ICD–11. The guidelines on considering psychoactive substances for international
control, which is a function of the WHO Expert Committee on Drug Dependence, use the terms
“dependence–producing” and “dependence” as well as “abuse.” “Abuse” is not anymore a part of WHO
nomenclature, but this term is used in the international drug treaties and within the discourse relevant to
international control of psychoactive drugs and drug treaties. In WHO recent documents, the term
“psychoactive drugs” does not include alcohol and nicotine, which, in combination with psychoactive
drugs, are covered by the term “psychoactive substances.” In the World Drug Report, the term ATS covers
amphetamine, methamphetamine, methcathinone, and the “ecstasy”-group substances (3,4-
methylenedioxymethamphetamine [MDMA] and its analogues).
SECTION 5
Special Issues in Addiction

CHAPTER 37
Prescription Medications: Nonmedical
Use, Use Disorders, and Public Health
Consequences
Wilson M. Compton, Christopher M. Jones and Maureen
P. Boyle, and Eric M. Wargo
CHAPTER OUTLINE
Introduction
Historical Perspective on the Scheduling of Prescription Drugs in the
United States
Definitions of the Terms Used to Classify Subtypes of Nonmedical
Medication Use
Epidemiology of Nonmedical Use of Prescription Drugs
The Major Classes of Prescription Drugs Used Nonmedically
Evidence-based Prevention and Harm Reduction and Policy Approaches
Evidence-based Treatment for Prescription Drug Use Disorders
Ongoing Research
Summary/conclusions
INTRODUCTION
Nonmedical use of pharmaceuticals has been a problem as long as such products
have existed, and the current patterns in the United States represent the newest
iteration (1). The list of medications that are used in a manner or for a purpose
not directed by a physician is lengthy, but the primary categories of clinical
importance are opioids, stimulants, and sedatives–hypnotics. The extent of the
problem (Fig. 37-1) is staggering, with national surveys showing that in 2015
approximately 18.9 million Americans ages 12 and older used opioid, stimulant,
or sedative–hypnotic medications nonmedically in the past year—with
nonmedical use of prescription analgesics (ie, opioids) the most often endorsed
—and over 2.7 million Americans meeting the criteria for a substance use
disorder related to nonmedical use of prescription drugs (2). In fact, nonmedical
use of prescription opioids has been implicated as a major component in the
nearly fourfold increase in drug overdose deaths in the United States between
2000 and 2014 (3). More recent data show that in 2016, drug overdose deaths
stood at a record 63,632 persons, with 17,087 of these deaths attributed to opioid
analgesics (4).
Figure 37-1. Past-year nonmedical use of prescription
psychotherapeutics among US persons age 12 and older,
2015. (From Center for Behavioral Health Statistics and
Quality. 2015 National Survey on Drug Use and Health:
Detailed Tables. Rockville, MD: Substance Abuse and
Mental Health Services Administration; 2016.)
Figure 37-2 Rates of prescription drug–related emergency

department visits, 2004-2011. (From Substance Abuse and
Mental Health Services Administration, Drug Abuse Warning
Network, 2011: National Estimates of Drug-Related
Emergency Department Visits. HHS Publication No. (SMA)
13-4760, DAWN Series D-39. Rockville, MD: Substance
Abuse and Mental Health Services Administration; 2013.)
Nonmedical use of prescription drugs is linked to medical practice in ways quite

different from alcohol, tobacco, and other illicit drugs. It presents unusual
difficulties for clinicians for two reasons. First, the medical system is the origin
of the substances in most cases. Prescription drugs are “legal” compounds,
manufactured by pharmaceutical companies and distributed by the medical
system before their diversion. Second, boundaries between therapeutic use,
nonmedical use, and addiction can be quite vague. Overall, prescribers are in a
unique situation of having to optimize medication dosage to minimize symptoms
of the disease being treated while also monitoring their prescribing practices in
order to reduce the risk of nonmedical use and addiction in their patients as well
as diversion to the larger community. But ultimately, prescribers can only control
what they prescribe, not how a prescription drug is taken.
In this chapter, several issues are covered: (a) historical perspectives on the
scheduling of prescription drugs; (b) definitions of the terms used to classify
subtypes of nonmedical prescription drug use; (c) epidemiology of nonmedical
prescription drug use; (d) review of the major classes of prescription drugs used
nonmedically (including a brief review of the pharmacology and neurobiological
effects of each category as well as the particular harms associated with the
category); (e) evidence-based prevention and harm reduction approaches
(including policy approaches); (f) evidence-based treatment for prescription drug
use disorders; and (g) ongoing research.
HISTORICAL PERSPECTIVE ON THE

SCHEDULING OF PRESCRIPTION
DRUGS IN THE UNITED STATES
Use of opioids to obtain euphoria dates to antiquity. In the late 19th century,
many Civil War veterans developed addiction to opioids (“the soldier’s
disease”), which began with exposure to injectable morphine for the treatment of
pain from their war-related injuries. Simultaneously, the patent medicine
industry was liberally promoting opioids and cocaine to treat a variety of
conditions. In response, the U.S. Harrison Narcotics Act was enacted in 1914 in
order to regulate and tax the production, importation, and distribution of opiates
and coca products.
More recently, in 1970, the Controlled Substances Act (CSA) was enacted to
regulate the manufacture, importation, possession, and distribution of drugs with
abuse liability and their precursor compounds. The CSA created drug Schedules
(classifications), based on whether a compound has an accepted medical use and
on its potential for misuse. This legislation also created the Drug Enforcement
Administration (DEA) within the Department of Justice, as the agency
responsible for enforcing the CSA and its implementation (5).
According to the DEA, Schedule I and II drugs have a high potential for
misuse (5). Schedule I drugs are only available for research and have no
approved medical use in the United States. Schedule II drugs are available only
by written prescription (paper or electronic); refills generally cannot be
authorized, and they require additional paperwork for ordering, storage, and
transfer. The DEA also sets annual production quotas for manufacture of these
substances. Schedule III and IV drugs are available only by prescription but have
a lower potential for misuse, and under the CSA, up to five refills in a 6-month
period may be authorized and may be ordered verbally (though state laws may
be more stringent). Schedule V drugs have lower potential for misuse than
Schedule IV medications, and some are available over the counter (dependent
upon state law). Scheduling is one mechanism that has been used to reduce
diversion of prescription drugs. For example, hydrocodone combination products
(eg, Vicodin and others) are the most commonly prescribed (6) and
nonmedically used (2) opioids, and their rescheduling from Schedule III to II in
2014 led to a 22% reduction in hydrocodone prescribing over the subsequent
year (7).
DEFINITIONS OF THE TERMS USED TO

CLASSIFY SUBTYPES OF NONMEDICAL
MEDICATION USE
In this chapter, nonmedical use of prescription drugs is generally defined as the
intentional use of a prescription medication in a way not intended by the
prescribing doctor. A prescription drug use disorder is a medical illness that
occurs when ongoing nonmedical use of prescription drugs leads to clinically
and functionally significant impairment, such as health problems, disability, and
failure to meet major responsibilities at work, school, or home. A moderate to
severe substance use disorder is commonly called an addiction (although some
use that vernacular term to mean any substance use disorder). It should be noted
that each source of epidemiological data uses slightly different versions of these
definitions, and so variation in results may partly be explained by these
definitional issues, although the underlying concepts are generally similar.
EPIDEMIOLOGY OF NONMEDICAL USE

OF PRESCRIPTION DRUGS
Nonmedical use of prescription drugs is associated with a diverse range of
potential health harms. Available epidemiological data include data from general
populations reflecting the overall scope of nonmedical use, emergency
department data demonstrating acute health harms, substance use disorder
treatment data, data estimating rates of infectious disease transmission among
people who inject prescription drugs, rates of neonates born with neonatal
abstinence syndrome (NAS), and overdose mortality data.
Approximately 7.1% or 18.9 million persons in the United States ages 12 or
older (Fig. 37-1) reported past-year nonmedical use of prescription drugs in 2015
(2). Analgesics were the most common class of medication used nonmedically,
followed by sedatives–hypnotics and stimulants. Hydrocodone and oxycodone
are the most commonly reported opioids used nonmedically (2), but virtually all
the opioids, especially higher-potency agents such as oxymorphone,
hydromorphone, and fentanyl (both prescription and also illicitly manufactured
versions), are reported frequently by treatment-seeking populations.
Nonmedical use of these substances was most prevalent in young adults
(ages 18-25), followed by adolescents (ages 12 to 17) and adults (ages 26+). In
general, males had slightly higher rates of nonmedical use, with an important
exception that adolescent females (ages 12 to 17) were more likely than males to
have used prescription drugs nonmedically (6.4% vs. 5.4%). Nearly 70% of high
school seniors who use prescription drugs nonmedically also report use of
alcohol, marijuana, and other substances, suggesting that nonmedical use of
prescription drugs is a potential indicator for broader substance use problems in
this population (8).
In 2015, over 2.7 million Americans met the criteria for a substance use
disorder related to nonmedical use of prescription drugs—including over 2
million who used prescription analgesics, 688,000 who used tranquilizers,
426,000 who used prescription stimulants, and 154,000 who used sedatives (2).
Emergency department data show marked increases in rates of prescription
drug–related mentions. Rates of prescription drug–related emergency department
visits more than doubled between 2004 and 2011 (from 535,447 to 1,244,872)
(9). Prescription opioids increased from 172,738 to 488,004, sedatives–hypnotics
from 177,409 to 421,940, and stimulants from 9979 to 40,648 (Fig. 37-2).
Treatment admissions related to prescription opioids also more than doubled
between 2004 and 2014 (10). Rates of overdose mortality associated with
prescription opioids (Figs. 37-3 and 37-4) have also increased markedly
throughout the United States between 1999 and 2015, but the increases are more
pronounced in certain high-risk areas including Appalachia. The coingestion of
benzodiazepines with opioids is responsible for an increasing percentage of
overdose deaths. More than 85% of overdose deaths involving benzodiazepines
also involved opioids, and 27% of prescription opioid overdose deaths involved
benzodiazepines in 2015 (11). Recent studies have also raised the possibility that
interactions between opioids and some antidepressant medications—specifically
selective serotonin reuptake inhibitors (SSRIs)—may increase the risk for
overdose by increasing the risk for serotonin syndrome (12).
Figure 37-3. Prescription opioid, heroin, and fentanyl

overdose deaths in the United States, 2000-2015. (From Rudd
RA, Seth P, David F, et al. Increases in drug and opioid-
involved overdose deaths — United States, 2010–2015. Morb
Mortal Wkly Rep (MMWR). 2016;65:1445–1452.
doi:10.15585/mmwr.mm655051e1.)
Figure 37-4. Estimated age-adjusted death rates for drug

poisoning by county in the United States in 1999 and 2015.
(Source: https://www.cdc.gov/nchs/data-visualization/drug-
poisoning-mortality/ Accessed April 24, 2017.)
Nonmedical use of prescription opioids has also been associated with increased
transmission of infectious diseases including hepatitis C (HCV) and HIV due to
sharing of needles and syringes by people who inject drugs, especially among
young people who inject drugs in suburban and rural areas (13,14). It has been
estimated that the annual incidence of HCV infection among young people who
inject drugs is between 8% and 25%, and currently, over 200 000 may be
infected. In the recent outbreak of HIV in Scott County, Indiana, in which 181
patients were newly diagnosed with HIV in under a year, over 92% were
coinfected with HCV (13).
The HCV virus is roughly ten times more infectious than HIV and lives
longer outside of the body, which translates to an increased risk for infection
among people who inject drugs. Recent analyses have found that regional rates
of HCV are correlated with the severity of the opioid overdose epidemic (15),
with reports suggesting that prescription opioid injection may be a stronger risk
factor than heroin or other drug injection (16).
Nonmedical use of prescription drugs is also a significant issue among
pregnant women. Although pregnant women generally consume fewer
substances than nonpregnant women, there was a dramatic fivefold increase in
rates of NAS in newborns of opioid-using women between 2000 and 2012 (17).
The increase in maternal opioid use and NAS was even more pronounced in
rural areas (18). Treatment of women with opioid use disorder can utilize either
methadone or buprenorphine to manage their opioid use during pregnancy. Some
studies have found that treatment of pregnant women with opioid use disorder
with buprenorphine can decrease the length of the hospital stay compared to
methadone management. However, research suggests that there may be
differences in treatment engagement and retention associated with
buprenorphine versus methadone treatment and that providing divided doses of
methadone may reduce the incidence of NAS (19). These findings highlight the
need for more research in this area. The primary goal is always stable reduction
of fetal and neonatal stress, with costs and length of stay as secondary factors.
Comorbidity with Other Substances and with

Psychiatric Illnesses
In general, there is a high rate of comorbidity between addictive disorders and
psychiatric disorders (20–22). DSM-IV-TR defined abuse and/or dependence on
one type of prescription drug are highly predictive of a clinically significant drug
use disorder related to another prescription drug, to an illicit drug, and/or to
alcohol (23–25). Prescription opioid use disorders, specifically, have been shown
to overlap considerably with other substance use disorders (23–26).
Less is known, however, about the timing of onset of comorbid disorders. In
one study, a prominent pathway from depressive spectrum disorders to
nonmedical use of prescription opioids was reported (27). In addition, recent
work is showing that nonmedical use of prescription drugs is generally part of a
polydrug use phenotype rather than a solitary condition (28). Overall, common
mental health disorders and problem drug use are associated with nonmedical
use of prescription drugs, even though causality often cannot be determined.
Clinicians need to carefully assess for co-occurring mental health and substance
use disorders whenever nonmedical use of prescription drugs is found.
THE MAJOR CLASSES OF
PRESCRIPTION DRUGS USED
NONMEDICALLY
The division of drugs into classes is based on the pharmacological activity of the
drug. Although anticholinergics, laxatives, neuroleptics, antidepressants, and
other drug classes can be used nonmedically, this chapter is limited primarily to
prescription opioids (analgesics), stimulants, and sedatives–hypnotics, each of
which share chemistry and physiological effects with illicit compounds in the
same class. Strategies for detoxification and treatment can be found in the
chapters specific to those drug classes. Nevertheless, diagnosis and management
of nonmedical use of prescription drugs may have unique features, such as co-
occurrence of a condition (eg, pain, anxiety, mood, or sleep disorders) for which
the drug may have originally been prescribed.
Another issue of growing importance is how to conceptualize the use of
cannabis as medicine. As of the writing of this chapter, 29 states had taken
legislative action to legalize cannabis as medicine despite the lack of medical
consensus around such use, and eight states plus the District of Columbia had
legalized its recreational use by adults. So far, data suggest that there is
significant overlap in the demographic factors that predict medical and
recreational use of cannabis (29); and in states with permissive regulations for
medical use, it is not clear that the medical distinctions are meaningful. Thus,
medical cannabis is not included in this chapter.
Opioids (Analgesics)
Chronic pain is highly prevalent in the United States (30), and opioids are a
common treatment despite long-standing recognition that not all pain syndromes
are responsive to opioid therapy and that addiction can arise from such use
(31–34). Following a period in which physicians had shied away from using
opioids due to this danger, a confluence of events converged to reverse this trend
in the 1990s. In 1996, Purdue Pharma released a new extended-release
formulation of oxycodone, OxyContin, and launched an aggressive marketing
campaign promoting its use and convincing prescribers that the risk for addiction
was “less than one percent.” Meanwhile, increasing recognition among the
medical community of the undertreatment of pain led the American Pain Society
to advocate for making pain a “fifth vital sign.” In response, most states became
more permissive in their policies regarding opioid prescribing and the Joint
Commission on Accreditation of Healthcare Organizations (now The Joint
Commission) promoted widespread assessment of pain in all patients as part of
their new pain management standards. Many clinicians consequently started to
prescribe opioids over extended periods for their chronic pain patients.
Interestingly, despite the well-established efficacy of opioids for treating
acute pain, there remains a dearth of evidence on the efficacy of opioids for
treating chronic pain (35); research also suggests that opioids may cause
hyperalgesia and exacerbate some chronic pain conditions. And while it was
once thought that the use of prescription opioids for legitimate pain treatment
was not associated with significant risk for nonmedical use or addiction, this is
now recognized to be incorrect; patients prescribed opioids legitimately to treat
pain are among those becoming addicted to these medications. Some studies
have estimated the prevalence of nonmedical use of prescription opioids among
patients with chronic pain to be as high as 25% (36), and another recent study
found that legitimate medical use of opioids before the end of high school was
independently associated with future use of opioids (37). Further adding to the
complexity of these issues, patients with severe debilitating pain may be
undertreated due to concerns about addiction (38,39). The difficulty of treating
pain while minimizing risk of addiction clearly presents particular complexities
for clinicians.
Key factors in the increase in prescription opioid deaths have been the
increases not just in opioid prescribing (3,40,41) but in prescribing of high-
potency opioids and high dosages, for longer durations, as well as the
coprescribing of benzodiazepines (11). In addition to national trends showing an
increase in deaths corresponding to the increases in prescribing, states with
higher rates of opioid prescribing tend to have higher rates of drug overdose
deaths (12,42,43). Additional evidence for this relationship comes from policy-
level interventions that addressed particularly egregious forms of
overprescribing (ie, “pill mills”). Florida instituted a series of major policy
changes in 2010 designed to reduce the inappropriate prescribing of prescription
opioids, including cracking down on pill mills, resulting in a curtailment of
prescriptions and a 27% reduction in overdose deaths related to prescription
opioids between 2010 and 2012 (44). Methadone used for pain management has
also received considerable attention as a contributor to the rise in prescription
opioid overdose deaths (45). Methadone has a long half-life with significant
variability across patients (ranging from 8 to 59 hours), substantially longer than
the duration of its analgesic effects (4-8 hours). This has resulted in
disproportionate involvement in overdose mortality in some states (45).
However, as efforts to focus on reducing the use of methadone for pain treatment
have emerged, there has been a decline in methadone prescribing that coincided
with a parallel decrease in methadone diversion and overdose deaths (45).
Another critical question is whether the nonmedical use of prescription
opioids leads to heroin use (3). While the majority of people who currently use
heroin report nonmedical use of prescription opioids before heroin initiation,
heroin use among people who nonmedically use prescription opioids is relatively
rare, with heroin onset at a rate of about 1% to 3% per year (46,47). As has been
documented extensively, heroin initiation is predicted by more frequent
nonmedical use of prescription opioids, presence of a prescription opioid use
disorder, injection of prescription drugs, and polysubstance use (3). The
transition from nonmedical use of prescription opioids to heroin use appears to
be part of the progression of addiction in a subset of individuals with nonmedical
use of prescription opioids driven in part by the availability of high purity, low
cost of heroin. As a person’s tolerance outstrips the dose of opioids they are able
to obtain from their providers, they may turn to the illicit market for pills or
heroin.
Heightening the sense of urgency for addressing this problem is the recent
increase in the use of illicitly produced fentanyl—a synthetic prescription opioid
50-100 times more potent than morphine, manufactured in clandestine labs and
commonly mixed with heroin or sold alone in powder form or as counterfeit
tablets. In 2016, there was a marked increase in overdose deaths involving
synthetic opioids other than methadone, a category dominated by fentanyl (4).
Epidemiological data indicate the population of individuals using fentanyl is
similar to that using heroin (48,49). Fundamentally, prescription opioids, heroin,
and emerging synthetic opioids such as fentanyl are each elements of a larger
epidemic of opioid-related morbidity and mortality. Viewing them from a unified
perspective that takes into account the interrelated factors that contribute to their
use and the natural history of the transition from nonmedical use of prescription
opioids to heroin use is essential to improving public health (3).
Stimulants
When used as directed, the side effects of prescription stimulants are typically
mild and include headaches, decreased appetite, weight loss, and insomnia.
However, nonmedical use (which typically includes use at higher dosages)
increases the risks for significant health effects including psychosis, cardiac
events, seizures, and sudden death.
High rates of nonmedical use of prescription stimulants may be related to
high rates of prescribing of these agents for attention deficit hyperactivity
disorder (ADHD); however, a specific association of prescribing increases to
changes in rates of nonmedical use of or harms from stimulants has not been
established (in contrast to opioids, where increased prescribing has been
unequivocally associated with increasing morbidity and mortality). Youth in the
United States are treated with stimulants for ADHD more frequently than in
Western European countries (50), and the number of prescriptions for children
and adults being treated for ADHD has increased markedly since 1990 (51,52).
For example, the amount of methylphenidate approved for production in the
United States increased over 47-fold from 1768 kg in 1990 to 84 375 kg in 2015
(53,54). However, unlike opioids for long-term treatment of chronic pain,
longitudinal studies have shown that pharmacological treatments with stimulants
are effective long term for ADHD (55). Another key difference from opioids is
that nonmedical use of stimulants used to treat ADHD may be more common
among friends/peers of youth prescribed these medications rather than the
individuals with the prescription themselves (56,57). Adolescent ADHD patients
show lower rates of stimulant use than other young people; however, these same
patients are often part of a sharing/diversion pathway for friends and classmates.
Nonmedical use of amphetamines (and other pharmaceutical stimulants) has
been relatively highly prevalent among youth for many years (58). Preference
for Adderall has been reported by both college and high school students (59).
National data show that stimulants are among the only substances used more by
college students than by their non–college-attending same-age peers (60). The
reasons for using stimulant medication nonmedically in college are varied and
include weight loss, improving attention, partying, reducing hyperactivity, and
improving grades (and sometimes a combination of the three—staying up to
party and then using again to stay up to cram) (61). Research also suggests that
students often lack an appreciation for the potency and potential health effects of
nonmedical stimulant use; because these are prescription substances, they are
perceived to be “safe.” Further, they are falsely perceived as enhancing academic
performance when the opposite is actually found when used nonmedically
(61,62).
Sedatives–Hypnotics
The category of sedatives–hypnotics is often divided into separate classes of
drugs based on their intended primary purpose—either relief from anxiety or
insomnia. With respect to the benzodiazepines, this division is not based on the
pharmacological properties of the medication but often only on dose
administered or the time of administration (ie, at bedtime or not), and for that
reason, we discuss them as one class.
Prescription sedatives–hypnotics have been used nonmedically for decades,
whether it was the earlier agents, such as the barbiturates and chloral hydrate, or
the benzodiazepines available since the 1960s. Some have proven to be highly
problematic and addictive (eg, methaqualone and the short-acting barbiturates)
and are no longer accepted as standards of care except in limited circumstances
—such as in hospitalized patients and in some cases of sedative detoxification—
but all have significant nonmedical use liability. Even the newest hypnotic
agents, such as zolpidem and zopiclone, while shown to have lower potential to
be used nonmedically than many earlier agents, have nonetheless been
associated with such use (63). Similar to the opioid and stimulant drugs classes,
there has been an increase in the prescribing of benzodiazepines, which could
account for increases in the nonmedical use of these drugs (64).
Although benzodiazepines alone do not typically cause overdoses, they have
been linked to a growing number of overdoses and fatalities involving other
drugs (11,12). In 2015, for example, over 8700 people died of an overdose
related to benzodiazepines. They are particularly lethal when combined with
other respiratory depressants including alcohol or opioids. Although the precise
pharmacological interactions are not fully known, some research has suggested
that benzodiazepines may modulate the pharmacokinetics of opioids, for
example, by inhibiting opioid metabolism (65). A large study of nonfatal opioid
overdoses found that 56% of patients obtained a benzodiazepine prescription in
the 90 days before the overdose (66).
An additional concern with sedatives is that withdrawal from these
medications can pose significant health risks, including seizures. Thus,
discontinuation of sedatives should be medically monitored.
EVIDENCE-BASED PREVENTION AND

HARM REDUCTION AND POLICY
APPROACHES
Prevention Programs
There are many evidence-based strategies to prevent or reduce nonmedical use
of prescription drugs and to reduce associated harms. Broad-based prevention
approaches, including universal family-based interventions such as the
Strengthening Families Program: For Parents and Youth 10-14, a family-based
program for younger adolescents, and PROmoting School-community-university
Partnerships to Enhance Resilience (PROSPER), a system for delivering
evidence-based interventions during grades 6 and 7, have been demonstrated to
reduce nonmedical use of prescription drugs (67). These approaches target
families as key agents to address a range of adolescent-onset risk behaviors. The
2017 Surgeon General’s Report, Facing Addiction in America, highlights the
need to increase the implementation of evidence-based prevention practices both
in the community and throughout healthcare systems (68).
Prescriber Education
The ongoing opioid overdose epidemic has highlighted the need to improve
provider education and equip providers with the tools they need to improve
prescribing practices. In March 2016, the Centers for Disease Control and
Prevention released a Guideline for Prescribing Opioids for Chronic Pain (see
Table 37-1 for a summary of recommendations) (69). This guideline provides
recommendations to limit short-term opioid prescriptions and summarizes recent
research on the use of opioids in the treatment of chronic pain. It is important to
recognize that this guideline provides general recommendations that may need to
be modified in caring for an individual patient. For example, opioid analgesic
metabolism varies markedly between individuals, so doses should be adjusted
based on individual patient response, even though the overall risk of overdose is
generally higher as doses are increased. In addition, while opioid equivalency
tables enable general comparison of the potency of various opioids, there is
significant interindividual variation; when shifting from one opioid to another,
caution in initial dosing is prudent.
TABLE 37-1 Summary of CDC Guideline for

Prescribing Opioids for Pain
Prescription Drug Monitoring Programs
Another strategy for improving prescribing practices for substances with liability
for nonmedical use is increasing the use of prescription drug monitoring
programs (PDMPs), which have been implemented in almost every state in the
United States and typically track prescribing of all controlled substances in
Schedules II to V. They are designed to identify risky prescribing patterns and
alert prescribers, pharmacists, and, in some states, law enforcement officials to
potential problems with the prescribing and use of controlled substances (70).
Enabling prescribers to access PDMP data in a rapid, automated manner can
inform clinicians about other controlled substances that may have been
prescribed to their patients. Such information can change prescribing practices
and has been shown to be effective when implemented fully (71,72). Yet,
physician enrollment and utilization continue to be rate-limiting factors in some
locations due to variations in state requirements for use, technology maturity,
and interoperability with electronic health records (71). A number of
jurisdictions around the country have passed laws requiring prescribers to check
the PDMP before prescribing controlled substances, and recent research found
that states with PDMPs that monitored all drug schedules (II to IV) and update
data at least weekly had lower opioid-related overdose death rates, compared to
other states with less robust PDMPs (71,72).
Abuse-Deterrent Formulations
Another strategy for reducing nonmedical use of prescription drugs is the
development of tamper-resistant drug formulations. These pharmaceutical
approaches include efforts to reduce the administration of prescription drugs
through unintended routes, via formulations that are designed to render a drug
ineffective if injected, insufflated, crushed, or dissolved (73). While some
evidence suggests that implementation of a tamper-resistant formulation of
OxyContin reduced nonmedical use of that specific agent (73,74), other research
suggests that high-risk groups of individuals who use opioids continued to report
nonmedical use of OxyContin after the reformulation (75). In addition, the
outbreak of HIV detected in Indiana in 2015 was primarily among persons who
injected extended-release oxymorphone, which had been reformulated in 2012
(13). This formulation has also been implicated in an outbreak of thrombotic
thrombocytopenic purpura (76). Overall, this data suggests caution in
anticipating the impact of reformulated opioids purportedly designed to reduce
harms (77).
Harm Reduction Policies

Other evidence-based strategies can be used to reduce the health harms
associated with nonmedical use of prescription drugs, including increasing
access to the opioid overdose reversal drug naloxone as well as providing people
who inject drugs with comprehensive services such as access to sterile syringes
and other injection equipment and testing, prevention, and treatment services for
HIV and HCV. For a full discussion of the concepts of harm reduction,
controversies surrounding them, and how they apply to addiction issues more
broadly, readers are encouraged to consult the chapter on harm reduction in
section 4 of this textbook.
Naloxone
Direct approaches to reducing overdose mortality include widespread
dissemination of opioid overdose education and naloxone (Narcan) distribution
(OOEND), with naloxone being a safe and effective medication for the acute
treatment of opioid overdose (78,79). Its use is standard practice in emergency
settings, where it can safely and quickly reverse an opioid-induced coma or
respiratory depression because of its rapid action as a μ-opioid receptor
antagonist. Increasing ready access to naloxone for opioid overdose reversal
shows promise in reducing overdose mortality among individuals who use
heroin and in communities hard-hit by overdoses (79–82). In addition,
coprescribing of naloxone self-injection kits or nasal spray to persons receiving
high-dose opioids for chronic pain is associated with reduced risk of emergency
department treatment for opioid complications (83). This is particularly
important, as early evidence suggests that patients on opioids for chronic pain
have significant numbers of opioid overdose risk factors and have witnessed or
personally experienced overdoses in significant numbers, yet they perceive their
own personal risk for overdose as lower than the general population (84,85).
Autoinjector and nasal spray formulations were approved by the U.S. Food and
Drug Administration in 2014 and 2015, respectively, and should facilitate
increased use by people without medical training.
Despite its potential to save lives, the public health impact of OOEND has
not yet reached its full potential (80). In addition, current formulations of
naloxone may not be sufficient to reverse an overdose on fentanyl or other
highly potent opioids. As the rate of fentanyl overdoses is rapidly increasing, it
should be recognized that multiple doses may be needed to revive someone
experiencing an overdose. It is also important for first responders to know that,
while fentanyl has a short duration of action (30-90 minutes), it can stay in fat
deposits for hours, and patients should be monitored for up to 12 hours after
resuscitation. More research is needed to develop new naloxone formulations
tailored to higher-potency opioids. In addition to expanding access to naloxone
to the full populations who could benefit, a key next step includes determining
the best ways to link persons who have been resuscitated to substance use
treatment (ie, transforming the rescue into a longer-term intervention
opportunity).
Needle and Syringe Services Programs

Sharing injection equipment poses significant risks for transmission of infectious
diseases. One policy that has repeatedly been proven effective for reducing the
spread of infectious diseases is access to sterile syringes and other injection
equipment. Syringe exchange was implemented in Indiana in response to the
prescription opioid-driven HIV outbreak and played a significant role in
containing the outbreak (86). In addition to reducing infectious disease
transmission, these programs also offer counseling services, HIV testing, and
referral to substance use disorder treatment services as well as safe disposal of
injection equipment.
HIV Prevention and Treatment

The seek, test, treat, and retain model of care (STTR), also known as the HIV
Care Continuum, involves reaching out to high-risk, hard-to-reach populations
who use substances and have not been recently tested for HIV; engaging them in
HIV testing; initiating, monitoring, and maintaining combined antiretroviral
therapy (cART) for those testing positive; and retaining patients in care.
Research has shown that implementation of STTR has the potential to decrease
the rate of HIV transmission by more than half (87). Multiple interrelated
mechanisms may account for this, including dramatic decreases in viral load
from antiretroviral medications and significant increases in related medical care
(including access to substance use disorder treatment).
Prescription Take-Back Programs

Many persons who use prescription drugs nonmedically do not obtain them
directly from physicians. For example, data from the National Survey on Drug
Use and Health (Fig. 37-5) document that the major sources for nonmedically
used prescription opioids are family and friends who have their own
prescriptions. (Note that persons who frequently use prescription opioids
nonmedically and those who are in treatment for opioid use disorders are more
likely to obtain opioids from drug dealers and from personal prescriptions.)
(88,89) In response, efforts are underway to make it easier for patients to discard
partially used prescriptions. While little empirical data addresses the
effectiveness of take-back programs in reducing the rates of nonmedical
prescription drug use or in reducing the harms from such use, these programs
show promise in removing unwanted, commonly nonmedically used medications
from people’s medicine cabinets (90), where they not only remain available for
nonmedical use by the intended recipient but may also be found and taken by
family members and visitors. They also serve as an opportunity to amplify
public messages about appropriate use, storage, and disposal of medications.
EVIDENCE-BASED TREATMENT FOR

PRESCRIPTION DRUG USE DISORDERS
The class of medication being used (opioid, stimulant, or sedative–hypnotic)
determines the appropriate type of care for an individual with a prescription drug
use disorder. Treatment for individuals with opioid use disorder will generally be
the same, whether the person uses prescription opioids or heroin. The opioid
agonist medication methadone and the opioid partial agonist medication
buprenorphine are effective for the treatment of all opioid use disorders and have
been shown to decrease opioid use, opioid overdose deaths, infectious disease
transmission, and criminal justice involvement while increasing social
functioning and retention in treatment (91,92). The opioid antagonist medication
naltrexone has also demonstrated efficacy in reducing illicit opioid use, but
compliance and retention in treatment hinder this drug’s utility; the extended-
release version may be an appropriate treatment for some individuals, especially
those who are highly motivated (93). Just as for heroin use disorder, tapers and
drug-free approaches for prescription opioid use disorder show significant risk of
relapse (91). No medications are currently FDA approved to treat stimulant use
disorders or sedative use disorders, but these prescription stimulant or sedative
use disorders are treated with the same behavioral therapies as other substance
use disorders. The same general principle applies to withdrawal syndromes—
namely, that treatment of prescription-related withdrawal is based on the drug
class, not whether it is a prescription-type drug. Of course, the pharmacokinetics
of the particular agent will influence acute care, and readers are encouraged to
consult other relevant sections of the textbook for details. It is also the case that a
person with a prescription drug use disorder may have comorbidities for which
they may have originally been prescribed the drug (eg, pain in the case of an
opioid use disorder), and such comorbidities must be addressed as part of
treatment.
Figure 37-5. Source where respondents age 12 and older
obtained their most recent analgesic that was nonmedically
used, and source where their friends/relatives obtained the
analgesic. (Source: Substance Abuse and Mental Health
Services Administration, 2012 and 2013 National Surveys on
Drug Use and Health.)
ONGOING RESEARCH
Although studies show that current best practices can be effective for reducing
nonmedical use of prescription drugs and its resulting harms, there is much room
for improvement. In the shorter term, research is underway to test and improve
prescribing approaches based on current knowledge about minimizing risk for
diversion, nonmedical use, and harm; to develop tamper-resistant formulations to
minimize intranasal and injection use of all prescription drugs; and to maximize
the uptake of effective approaches for reducing and treating nonmedical use of
prescription drugs (ie, implementation research).
Over the longer term, research aims to develop new treatments for pain,
ADHD, anxiety, and insomnia (ie, the main indications for analgesics,
stimulants, and sedatives–hypnotics, respectively) with reduced potential for
nonmedical use and/or overdose and better understand the neurobiology of
substance use disorders as a foundation for developing better prevention and
treatment approaches (ie, basic science research).
SUMMARY/CONCLUSIONS
Opioids have a role to play in the management of certain types of pain, but
prescription opioid overdose deaths have escalated in conjunction with
increasing numbers of prescriptions. In response, several strategies are being
implemented both nationally and at the state and organizational levels. Strategies
to reduce the supply of controlled prescription drugs available for nonmedical
use and diversion include PDMPs and related policies to promote their use, law
enforcement efforts to shut down pill mills, moving problematic opioids to
Schedule II, prescriber education including issuance of new prescriber
guidelines, public education and prescription take-back events, and evidence-
based drug use prevention programs.
Being aware of and adhering to improved prescription guidelines and
improved training in pain management are the responsibility of healthcare
systems and clinicians. Alternate approaches to pain management already exist
and should be tried before opioids are considered; they include psychosocial
approaches (eg, cognitive–behavioral therapy) and nonopioid medications (eg,
nonsteroidal anti-inflammatory drugs [NSAIDs], antidepressants, and
anticonvulsants), TENS units, and exercise therapy. Routine use of PDMP data
prior to writing prescriptions for controlled substances must also become
standard practice. And given potential liability issues (eg, potential lawsuits for
underprescribing and prosecution for overprescribing), well-written medical
records and documented consultations are now an essential part of pain
management. Good clinical practice includes meticulous medical records that
document the logic for dosages (especially increases), and if a patient is not
responding to standard treatment or requires dosage increases, written
consultation may be warranted. Finally, just as attention to PDMP data is
recommended, clinicians should document and respond to clinical signals of
inappropriate medication usage such as repeated early refills, lost prescriptions,
and lack of compliance with recommendations.
Physicians should also be better trained to detect nonmedical prescription
drug use (and other substance use) through screening and to treat patients’
substance use disorders. Those in addiction treatment settings or otherwise able
to prescribe medications for opioid use disorders (methadone and
buprenorphine) should not hesitate to use these effective tools. Research has
repeatedly shown these medications to be effective and cost-effective for
reducing opioid use and a wide range of related outcomes. Low adoption of
these treatments due to infrastructure impediments and lingering stigma must, in
the light of the evidence, be seen as medically irresponsible and a contributor to
the current scope of the opioid crisis. Effective utilization of medications means
prescribing them at the recommended dose and for a sufficient duration (which
may be indefinitely). Extended-release naltrexone has also shown efficacy
despite the compliance issues that hinder its effectiveness and may be an
appropriate alternative for some patients. Improving access to these treatments
will also depend on better integration of substance use disorder treatment within
general health care.
Harm reduction strategies like syringe services programs and naloxone
distribution are essential to reducing significant health consequences of
nonmedical prescription drug use. Syringe services programs can reduce the
spread of HIV and HCV as well as link people who inject drugs to treatment.
Providing naloxone in an easy-to-administer formulation to those at risk of
opioid overdose (eg, people with opioid use disorders and those receiving high
dosages of opioids or potent formulations) and potential bystanders can save
lives; and reversing an overdose with naloxone can be a critical opportunity for
engaging patients in substance use disorder treatment, as has been shown for
emergency department patients (94). Unfortunately, despite studies showing that
syringe services programs and naloxone distribution do not increase drug use in
communities that implement them, long-standing attitudinal barriers to harm
reduction impede their adoption (95,96).
When it comes to nonmedical use of prescription drugs, physicians find
themselves on the horns of a dilemma. They are the principal “supply” of these
substances while also being the first line of defense against their diversion and
nonmedical use. These complexities require the exercise of caution in addition to
compassion. To accomplish this, physicians need to be knowledgeable about the
conditions addressed by these medications (pain, anxiety, ADHD, etc.) as well as
the potential of these medications to lead to substance use disorders both in their
patients and in the wider community. This requires physicians to keep up to date
with the latest prescribing guidelines and employ evidence-based strategies to
prevent and treat addiction.
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CHAPTER 38
Special Issues in Treatment: Women
Joan E. Zweben
CHAPTER OUTLINE
Introduction
Epidemiology
Medical Considerations
HIV/AIDS
Psychiatric Disorders
Special Populations
Treatment Issues
Conclusions
INTRODUCTION
Gender disparities in the treatment of women were largely ignored until the
1970s, when interest grew in the biomedical and psychosocial aspects of
women’s use of alcohol and other drugs. Pressed by the women’s movement, the
federal government funded efforts to focus scientific and public attention on
women’s issues (1,2). This generated new research and services specifically
tailored to women’s needs, new materials for clinicians in the field, and
reconsideration of public policy.
Although a growing number of programs are providing services specifically
for women, there still are many ways in which the needs of women in alcohol
and drug treatment remain unmet. According to Substance Abuse and Mental
Health Services Administration’s (SAMHSA’s) Facility Locator (2014 data),
44% of the 14 152 programs listed offered specific services for women, up from
24% in 2007 (3).
EPIDEMIOLOGY
Gender Differences in Alcohol and Other
Drug Use
Reported rates of drug use are becoming more similar for men and women with
each passing decade. Several large-scale epidemiological studies find higher
rates of alcohol and other drug use in men (4,5). The Epidemiological Catchment
Area (ECA) study, with data collected in the 1980s, reported that men had five
times greater 1-month prevalence rates for alcohol and three times greater 1-
month prevalence for other drugs (5). The 1994 National Comorbidity Study
(NCS) (4,5) documented similar differences, but the gap is diminishing. A
subsequent National Survey on Drug Use and Health (NSDUH), conducted in
2010, showed smaller gender differences for all age groups except adolescents
aged 12-17 years. For this group, the gap virtually disappeared for alcohol,
marijuana, cocaine, and cigarettes. Although men have historically used heroin
at higher rates, recent demographics show an increasing percentage of non-
Hispanic white women. It is possible that this partly reflects the increase in
individuals with higher incomes and private insurance (6).
Common Psychiatric Disorders in Women

With Substance Use Disorder
Most men and women in treatment for substance use disorder have at least one
coexisting psychiatric disorder, but the pattern differs by gender. Both the ECA
Study (4,5) and the NCS (4) found that women were more likely to have
affective disorders than men (with the exception of mania, for which rates were
the same). Women were significantly more likely than men to have experienced
a major depressive episode. Data from the NCS showed a lifetime prevalence of
21.3% and a 12-month prevalence of 12.9% for women, compared with 12.7%
and 7.7% for men. Dysthymia also was more common in women, with a lifetime
prevalence of 8% and a 12-month prevalence of 3% compared with 4.8% and
2.1% for men. Women also had a higher lifetime and 12-month prevalence of
three or more disorders. In addition, women who have experienced childhood
sexual abuse (CSA) are at greatly increased risk of developing a wide range of
psychopathology, particularly bulimia, alcoholism, and other drug dependence
(7).
MEDICAL CONSIDERATIONS
A steadily growing body of evidence indicates women are at higher risks for
developing health problems in multiple organ systems from a variety of
substances. In addition, women may be more vulnerable to the side effects of
medications used to treat substance use disorders (SUDs), and doses need to be
adjusted accordingly (8).
Alcohol
The influence of alcohol on women’s health has been much more extensively
studied than other drugs. Although women are less likely than men to drink
heavily or even moderately (9), when they do so, they are more vulnerable to
alcohol-related liver damage, cardiovascular disease, and neurological problems
(10). A large prospective study that followed 13,000 adults in Copenhagen for 12
years found that women developed alcohol-related liver disease at approximately
half the consumption levels of men (11). For women, the risk of alcohol-induced
liver disease and alcohol-related cirrhosis rose once consumption levels
exceeded 7-13 standard drinks (84-156 g of alcohol) per week. Alcohol
increased women’s susceptibility to myopathy and cardiomyopathy, and studies
suggest that alcohol-dependent females suffer from a generalized skeletal
fragility that increases their risks of fracture from falls (10).
Negative consequences occur at lower levels of consumption and after much
shorter periods of drinking. This is referred to as the “telescoped course” in
women. There is growing evidence that women develop many of the
pathological effects of alcohol more rapidly than men, including fatty liver,
hypertension, anemia, malnutrition, gastrointestinal hemorrhage, and peptic
ulcers requiring surgery (12). Some of the proposed mechanisms include a lower
body mass index, a smaller volume of total body water (more fat and smaller
water compartment for distribution), and lower rates of gastric alcohol
dehydrogenase (13), such that after an equivalent dose of alcohol, women have
higher blood alcohol level than men.
One review of studies of alcohol absorption, distribution, elimination, and
impairment explored the mechanisms by which women achieve higher blood
alcohol concentrations than men after drinking equivalent amounts of alcohol,
even when doses are adjusted for body weight (14). Women tend to have lower
levels of alcohol dehydrogenase and lower volumes of water compartment
distribution leading to an increased effect of alcohol from an equivalent exposure
in a man. They noted women’s relatively greater susceptibility to alcohol’s
effects on cognitive functions, such as impaired memory. They concluded that
the menstrual cycle is not likely to affect alcohol pharmacokinetics and is not a
significant influence on alcohol’s effects on performance.
Alcohol consumption raises breast cancer risk even after adjustment for age,
family history, and other known dietary and reproductive risk factors (10). The
increased risk appears to be modest and dose-related, and the form of alcohol
appears to be irrelevant. Late life increase in alcohol consumption in
postmenopausal women appears to be associated with greater risk (15).
Mechanisms for this increased risk are unknown.
It is important that clinicians make use of opportunities to educate women
about their greater risks, even for those who are highly educated and articulate
(16). There is still widespread public naivete about what constitutes moderate- or
low-risk drinking. Women surveyed interpreted their increased tolerance or the
absence of short-term negative consequences to mean they are drinking
moderately. None of the 150 respondents discussed gender differences in their
in-depth interview (16), indicating a surprising lack of awareness given how
long the public information on differential impact has been available.
Prenatal Alcohol Exposure

There is no demonstrated safe level of alcohol consumption at any time during
pregnancy. Drinking during pregnancy remains a serious concern, with
healthcare professionals in a key position to reinforce social norms that
encourage the elimination of drinking during this time.
Fetal alcohol spectrum disorder (FASD) refers to a group of conditions that
include both physical and behavioral problems. The most serious, fetal alcohol
syndrome (FAS), is a set of birth defects considered the single leading
nonhereditary cause of mental retardation. The growth deficiency and
characteristic set of facial traits tend to appear more normal over time, but the
alcohol-induced damage to the developing brain is enduring. Other fetal alcohol
impairments are dose related and include some physical abnormalities as well as
difficulties in learning and remembering, understanding and following
directions, controlling emotions, and communicating a socializing, daily life
skill, such as feeding and bathing (17).
Compounding these defects are the caregiving deficits in the child’s
immediate family when one or both parents are drinking heavily. These
psychosocial deficits include inconsistent nurturance; poor parental support,
inconsistent monitoring, and communication; high levels of family conflict; and
higher rates of physical and sexual abuse (18). Comprehensive treatment of the
substance-abusing woman needs to address these contextual needs and to assess
for antecedent traumas, as described later in this chapter.
Drugs
Although evidence for gender differences in the effects of drug use is not as
extensive as alcohol, there are indications that gender may be a factor.
Greenfield and colleagues (19) summarize sex differences related to responsivity
to drugs of abuse and to relapse, citing differences in hormonal activity, stress
reactivity, and neurobiological correlates documented in neuroimaging studies.
Women also show a telescoped course, an accelerated progress from the
initiation to the onset of dependence and first admission to treatment.
Stimulants
Women may be more at risk for using stimulants due to a combination of their
pleasurable reinforcing effects and the weakening influence of social protective
factors (20). A study of treatment-seeking women who use cocaine concluded
that some women may have greater vulnerability to the effects of cocaine
compared to men, resulting in more rapid progression of pathology (21).
Mechanisms suggested include female steroid hormones (22), estrogen (23), and
differences in receptor function (24). Recent investigations of the influence of
menstrual cycle phase have yielded contradictory results (25–27).
Heroin
There is a smaller literature on heroin use. Grella (28) documented that heroin-
using women report significantly more chronic health problems and
psychological distress, and overall poorer health status and mental health
problems. It is well known that a woman’s substance use is heavily influenced
by her male partner (29–32), and she can underestimate her level of harm if her
main reference point is comparing her own use to her partner’s behavior.
The prescription drug epidemic has fueled an upsurge in heroin use as
supplies become more expensive and/or less available. Women seeking
treatment constitute a significant segment of new heroin users (33).
Prescription Opioid Use Disorder

Nonmedical use of prescription opioids has been rising steadily since the late
1990s, with rates in women similar to those in men (34). For nonmedical use of
prescription opioids, risk factors vary by gender. In general, other alcohol and
illicit drug use disorders were associated with use of nonmedical use of
prescription opioids reported within the last year for both men and women. For
women, the distinctive gender-specific factors for nonmedical use were first use
of illicit drugs beginning at age 24 or older, serious mental illness, and cigarette
smoking (35).
Women are at risk for inadvertent overdose, given that they are more likely
to receive prescriptions for opioids and sedatives (36). Buprenorphine
monotherapy as well as methadone maintenance can be used with pregnant
women (37) with prescription drug use disorder.
Prescription drug misuse and opioid treatment will be covered in detail
elsewhere in this volume.
Interpersonal Violence
There is now very strong evidence that substance use plays an important role in
interpersonal violence, though it may be only one of many contributing factors.
If a comprehensive assessment indicates it is a major factor, integrated substance
use treatment is likely to yield the best results, though these are relatively rare in
community programs (38).
Domestic violence accounts for 21% of all violent crime, and the majority
(76%) is committed against women (39). Many of these women endure abuse for
many years, because they have difficulty effecting separations and utilizing
shelters to get away from their batterers. Women who have been battered report
that their general health is fair or poor, that they have had sexually transmitted
diseases and other gynecological problems, and that they have needed medical
care that they have not received. Chronic headaches, as well as hearing, vision,
and concentration problems, are common sequelae. A variety of stress-related
symptoms, such as irritable bowel syndrome, anxiety, and depression can also
manifest. For these reasons, psychosocial treatment must be integrated with good
medical care.
Violence in the family of origin, antisocial and/or aggressive behavior as a
teen, anger, substance abuse, relationship dissatisfaction, psychological
aggression, and power/control tactics have been shown to predict partner
violence (40). Careful assessment is needed because of patterns of secrecy and
because differing levels of partner violence will require different types of
interventions. The Conflict Tactics Scale (CTS) is well validated and widely
used for identifying partner violence (41). Clinicians need to know how to
develop a safety plan with the patients, when and how to treat the substance use,
when to utilize marital therapy, and how to avoid common mistakes such as
confronting the partner directly or allowing the partner to join the medical or
psychiatric interview. A special technical problem often confronted by clinicians
is a revelation of previously secret violence but linked to a plea not to reveal any
of that to the partner. Often, such “binds” can be discussed in team staff
meetings, so that a clinical consensus may be established and charted. Clinicians
need to know contact information for local shelters and other community
resources (40), and they need to be familiar with state reporting requirements for
domestic violence.
HIV/AIDS
Women represent 25% of people in the United States who are living with HIV in
2014. About 87% new diagnoses in women are attributed to heterosexual sex
and 13% attributed to intravenous drug use. An estimated 62% were African
American, 18% were white, and 16% were Hispanic/Latina. New diagnoses
have declined 40% between 2005 and 2014, with the greatest decline among
African Americans. Of women diagnosed in 2013, 84% were linked to care
within 3 months, but only 55% were retained, only 35% were prescribed
antiretroviral therapy, and only 30% had achieved viral suppression (42).
Socially sanctioned imbalance of power plays a major role in inhibiting risk
reduction actions in women. Because condoms remain the major method to
reduce sexual transmission of HIV, women remain at a disadvantage. Women
either must gain the cooperation of their male partners in using a condom or
must decide not to have sexual relations if the man refuses (43,44). Many
women lack the self-esteem and communication skills to negotiate condom use.
Young women in particular often lack the fortitude to insist if their partners balk.
Addicted women are at an additional disadvantage in attempting to practice safer
sex. Many women fear emotional or physical abuse if they do so. The future
development of an effective protective method that is under the woman’s control
and can be used without the knowledge of her sexual partner is a key goal for
reducing women’s risk.
For the HIV-infected women, managing caretaking responsibilities often is
an issue added to the physical and psychiatric burdens of the disease. They
worry about transmission of the virus to family members and must be both well
informed and reassured. They struggle with how to address their health issues
and their possible death with their children. Women who have given birth to
HIV-infected children have an added layer of anxiety and guilt. After delivery,
women in these circumstances are often socially isolated and welcome the
opportunity to share with other women in a support group, which can help to
reduce their shame and express their feelings more openly, with less fear of
rejection (45).
PSYCHIATRIC DISORDERS
The need for treatment interventions that are sensitive to gender differences has
brought increasing attention to co-occurring disorders and their effect on
addicted women. Although the addiction treatment field has made great progress
in addressing co-occurring disorders in the last several decades, advances in
understanding and practice vary greatly in their degree of dissemination. It is
still common for public sector addiction and psychiatric treatment to remain in
separate silos, with psychiatric resources focused on those with severe and
persistent mental illness. Many with other disorders fall into the addiction
treatment system, where access to psychiatry services can be challenging.
Physicians can expect wide variation in sophistication and responsiveness
among community providers and should attempt to refer or place the patient
where she is likely to get the specific services indicated by her specific
conditions and behaviors. These are described in the most recent revision of
ASAM Criteria (46).
The most common psychiatric disorders found in women with unhealthy
substance use are anxiety disorders (especially PTSD), mood disorders, eating
disorders, and borderline personality disorder.
Anxiety Disorders
As a group, these disorders constitute the most common psychiatric disorders
among women, with a total lifetime prevalence of 30.5% and a 12-month
prevalence of 22.6% (4). The experience of anxiety is characterized by
sensations of nervousness, tension, apprehension, and fear that arise from the
anticipation of internal or external danger. These feelings constitute important
survival signals (fight/flight responses), so the task is to distinguish what is
normal and appropriate from states that require intervention. Certainly, women
in early recovery will experience heightened distress as they try to cope with
situations in which they previously relied on alcohol and other drugs and also as
they more clearly see the impact of their self-destructive behaviors. However,
overwhelming anxiety is debilitating, interferes with new learning, and
contributes to relapse. Severe anxiety is associated with premature dropout from
residential treatment (47).
Psychosocial strategies are beneficial for the management of anxiety
regardless of whether it is normal or excessive. The task for the woman and the
treating clinician is to determine when the level is high enough to impair daily
function and to justify medication. Fortunately, the first-line medications for
anxiety and panic disorders are no longer the benzodiazepines, but the selective
serotonin reuptake inhibitors (SSRIs), historically mischaracterized as
antidepressants only.
It can be easy to underestimate her level of distress when a woman’s
description is viewed as “dramatic”; a century ago, women with such
presentations were dismissively labeled as “hysterics.” Both depression and
anxiety can occur in the context of a wide variety of other disorders, and it may
be difficult to disentangle the interacting elements and identify the predominant
disorders. When anxiety symptoms do not resolve with abstinence, a variety of
psychosocial interventions can be used, selected to address the tasks specific to
the woman’s stage of recovery. In early recovery, calming reassurance, reality-
oriented support, exercise, meditation, breathing management, and other
relaxation techniques can be helpful when added to group activities designed to
encourage exchange of experiences and transmission of skills.
In the later stages of treatment, a variety of supportive, cognitive, and
psychodynamic therapies can be used, but anxiety-arousing explorations should
be avoided in early recovery. Insight-oriented therapy should be used in the
context of a firm recovery support system (including regular self-help group
attendance) by a therapist familiar with recovery issues. Familiarity with relapse
hazards, warning signs, and prevention strategies are important. Severe or
chronic anxiety can be a significant relapse hazard, so it is important to develop
a medication stance that does not make a virtue out of excessive suffering. Some
clinicians are too quick to assume the patient is just intolerant of unpleasant
feelings and should learn to live with them. However, the patient must develop
new ways of coping with everyday distress, and it is undesirable to seek to
eliminate most of the unpleasant feeling states that are inevitable in recovery.
Benzodiazepines, commonly prescribed for anxiety disorders, are no longer
first-line drugs for the treatment of anxiety, and they can be particularly
problematic for those with a personal or family history of addiction. They are
best avoided when possible or used in circumscribed situations (48) when other
interventions have failed and use can be carefully monitored. Nonreinforcing
alternatives, such as sedating antidepressants or buspirone (BuSpar) for anxiety
or trazodone (Desyrel) for insomnia, and SSRIs are recommended alternatives.
Some anticonvulsants or the newer atypical neuroleptic medications can also be
used, though some have serious side effect profiles. When reasonable
alternatives have failed, benzodiazepines can be used with careful monitoring.
This includes consideration of abstinence from substances, adherence to
prescribed medication regimens, and participation in recovery efforts (48).
Posttraumatic Stress Disorder

Of all the anxiety disorders, posttraumatic stress disorder (PTSD) is arguably the
most difficult and complex to manage. In the NCS, the estimated lifetime
prevalence of PTSD was 7.8%, with a striking gender difference—a prevalence
of 10.4% in women as compared with 5.0% in men (49). An exception to this, in
this era of sustained international wars, may be found in male combat veterans
who have higher rates of deployment-related PTSD and women veterans who
report high rates of military sexual trauma (MST). This finding is consistent with
several studies by Breslau and colleagues (50–52). Wasserman and colleagues
(53) concluded that the association between female gender and PTSD is robust
across patient populations. Rape and sexual molestation were the most
frequently reported “most upsetting event(s),” with childhood parental neglect
and childhood physical abuse reported more frequently by women. Female
victims were more than twice as likely as male victims to develop PTSD (20%
compared with 8.2%). A lifetime history of at least one other disorder was
present in 79% of women with PTSD, and more than a third of the women with
PTSD failed to recover from their PTSD, even after many years and even if they
received professional treatment.
Participants in addiction treatment have much higher rates of traumatic
experiences and PTSD than the general population. Studies of both residential
and outpatient treatment programs that serve both middle-class insured and
indigent populations show high levels of childhood abuse and adult trauma
(53–59). These findings require treatment providers to equip themselves to meet
complex needs. As Brown and colleagues (60) demonstrated, such a high “level
of burden” promotes early dropout, increases the difficulty of treatment in a
variety of ways, and makes it more difficult to obtain a positive outcome.
Childhood traumatic experiences set the stage for later manifestation of a
wide range of disorders and enhance the likelihood of dysfunctional coping
responses in adulthood (61,62). Studies differ in terms of the types of trauma
they consider and how they measure it, making it difficult to compare across
studies. Russell and Wilsnack (63) discuss the methodological problems in
comparing the studies that started to emerge in the 1990s. They examined
available studies using a conservative definition of CSA that and included both
intrafamilial and extrafamilial sexual abuse, but excluded noncontact
experiences, before the age of 18. By these criteria, in community samples, more
than one-third of female children experienced sexual abuse by the age of 18
years. This included incest, defined as sexual abuse by a relative before the age
of 18.
More recent studies and reviewers support these findings. In a population-
based study of female twins, Kendler and his colleagues (7) found that 30.4%
reported CSA of a variety of kinds (sexual invitation, sexual kissing, fondling,
exposing, sexual touching), and 8.4% reported intercourse. They analyzed their
data to examine the relationship of CSA and common psychiatric disorders and
substance abuse, controlling for background familial factors. They concluded
that women with CSA are at high risk for developing a wide range of
psychopathology. In their 1995 National Comorbidity Study, Kessler and
colleagues (49) came to similar conclusions regarding the relationship between
sexual trauma, PTSD, and other psychiatric disorders in women. It is also worth
noting that the ACE (Adverse Childhood Experiences) Study (64) documented
that persons exposed to one category of adverse experiences (abuse or family
dysfunction) were likely to have been exposed to others, and this was associated
with greater health risk factors for leading causes of death in adults, including
heart disease, cancer, skeletal fractures, and liver disease (64). Thus, the impact
of abuse extends far beyond psychological injury.
Women in substance abuse treatment show higher rates of CSA than the
general population (65,66). Addictive disorder is only one of many sequelae.
Others include low self-esteem, depression, suicidal thoughts and attempts,
anxiety, difficulties in interpersonal relationships, sexual dysfunction, and a
tendency toward revictimization (53). These girls are at nearly a fourfold
increased risk of any psychiatric disorder and a threefold risk of addictive
disorder (67).
It appears that among adult stressors, rape is the most consistently severe in
its effect (50) and is associated with a range of psychiatric symptoms (68). Koss
and Burkart (69) noted that almost half of the victims of rape seek some type of
professional psychotherapy, often years after the assault. Women with histories
of sexual assault in both childhood and adulthood reported significantly greater
odds of lifetime suicide attempts (70). Intimate partner violence is especially
associated with suicidal ideation and other psychiatric symptoms (71).
Mood Disorders
In assessing depressive symptoms, it is important to rule out the direct effects of
alcohol, illicit drugs, or medications, as well as general medical conditions, such
as hypothyroidism. Providers should have protocols for assessing suicide risk
factors as well as protective factors. Please note that risk factors are not
predictors per se; they are reminders for more complete evaluation. These risks
are often, but not exclusively, linked to mood disorders. One may consider
suicide out of shame or failure as well as depression.
Pregnant patients with mood disorders fared worse on drug use outcomes
than those with an anxiety disorder or no co-occurring disorder (72),
highlighting the importance of rapid identification and intervention during
pregnancy. When antidepressant management is required during pregnancy,
there is a substantial literature on known pregnancy risks common
antidepressants (73,74).
For diagnostic purposes, negative mood states that are the direct effect of
alcohol or illicit drugs generally clear within 2-3 weeks, with symptoms of
longer duration suggesting an independent mood disorder (75). Distress or
dysphoria or guilt, which is not the same as major depression, can persist for a
long time. It is important to inquire carefully, because women in recovery often
use the term “depressed” to describe brooding anxiety, misery, obsessive guilt,
apprehension, and other forms of wretchedness that are not synonymous with
major depression.
It also is important to remember that a sad or depressed mood is only one of
many signs and symptoms of a clinically significant depression and may not be
the most prominent feature. Other indications include disturbances in emotional,
cognitive, behavioral, or somatic regulation. The mood disturbance itself can
include apathy, anxiety, or irritability along with, or instead of, sadness. Not all
clinically depressed patients feel sad, and many who feel sad are not clinically
depressed. Clinicians need to have good skills for drawing patients out and
helping them describe their feelings. Women in subcultures that place a high
value on functioning can mask depressive symptoms. Those in leadership or
caregiver roles can initially manifest depression in more disguised forms,
especially if they have a high investment in performance or in continuing to
function despite distress. Some depressed women do not describe a low mood,
but their interest in or capacity for pleasure or enjoyment may be markedly
reduced, making it difficult for them to experience rewards in recovery or to
invest in new social relationships with others who do not drink or use drugs.
Eating Disorders
Despite the recognition that eating disorders are relatively common in substance-
abusing women, careful assessment is not routine and integrated treatment is
rare. Eating disorders are more prevalent among substance-abusing women than
in the general population, and substance-abusing women report more disordered
eating behavior than women in the general population. Stimulants and over-the-
counter diet preparations are particularly appealing to women seeking to lose or
control weight. In many cases, the early appeal of stimulant use/abuse is the
associated loss of appetite. In another era, cigarette manufacturers touted the
anorectic benefits of smoking (Virginia Slims).
A 1994 review of the comorbidity of eating disorders and addictive disorder
(76) indicated that bulimia is more common than anorexia. Women with bulimia
and alcohol dependence are more likely to have major depression, drug
dependence, tobacco dependence, and obsessive compulsive disorder than
women with either disorder alone (77). Krahn and colleagues (78,79) studied
eating abnormalities and substance use (including alcoholism) and suggested
that levels of symptoms below the threshold required to meet criteria for eating
disorders are important for the clinician to address. They caution that dieting-
related attitudes and behaviors in young women may be related to increased
susceptibility to alcohol and other drug use.
Among women who use alcohol and drugs, there are many possible
relationships between substance use and eating disorders. The eating disorder
may present before the onset of alcohol and drug problems. Eating disorders can
coexist with substance use in a variety of ways. Some patients report that opioids
are appealing because they facilitate vomiting. Drinking alcohol can provide the
feeling of release also gained from vomiting. Stimulants are attractive because
they make women feel capable and energetic and suppress the appetite. Alcohol
can be used to suppress the panic associated with bingeing and vomiting or to
quash the shame that follows an episode. Eating disorders also can be part of a
pattern of symptom substitution in abstinent substance users. For example,
women concerned about weight gain once abstinent from stimulants may begin
to vomit or purge to cope with their anxiety about body image.
It is important for providers serving women to develop proficiency in
addressing eating disorders and obesity, especially given the demise of many
specialized eating disorder programs. Because secrecy is a feature of both
disorders, careful inquiry is important during the initial assessment, and
observation by staff members is necessary throughout treatment. A woman in
treatment may gain or lose 20 lb without a disorder being assessed and addressed
by her individual counselor or in her groups. Eating disorder specialists agree
that treatment of these conditions requires specialized training. A thorough
medical evaluation should assess possible problems, including metabolic
abnormalities and menstrual history, and be part of a plan for nutritional
stabilization, including strategies to stop aberrant eating behaviors, as well as
medication planning and discharge planning that actively addresses both
disorders (80).
Addiction specialists should avoid the temptation to apply a variant of the
Twelve Step model as the sole treatment for eating disorders and should be
selective about which elements are applied. Cognitive–behavioral approaches to
eating disorders, which are well supported by empirical evidence, are designed
to reduce dietary restraint (in contrast with promoting abstinence from particular
foods), address abnormal attitudes about body weight and shape, and alter
thinking about eating and personal control. Psychotherapy to address related
personal issues is encouraged much earlier in the recovery process (81,82) than
is the case with substance use disorder, and a strong therapeutic alliance
increases the likelihood of remission (81).
Borderline Personality Disorder

When receiving a patient with a borderline diagnosis, it is important to review
the diagnosis for accuracy. Unfortunately, misdiagnosis of borderline personality
disorder is quite common, because of conflation of borderline characteristics
with the demanding and manipulative behaviors exhibited during active alcohol
and drug use and early recovery. It was not until 1994, in the DSM-IV, that clear
criteria for differential diagnosis were introduced. These were retained in the
subsequent edition, DSM-V (83). Diagnoses prior to that time, or from settings
in which diagnostic rigor is not the norm, may be improperly classified. It is
often a residual term of art applied to the most difficult of behavioral
presentations. Thus, it is advisable to reconsider the diagnosis. This
reconsideration is especially important because borderline patients are viewed in
many settings as unrewarding to treat. Clinicians treating substance use disorder
are accustomed to seeing women present with behaviors consistent with
borderline personality disorder, who settle down markedly and look far less
pathological with a year or so of sobriety and a good recovery program.
Enduring characteristics of borderline personality disorder include unstable
mood and self-image; unstable, intense, interpersonal relationships; extremes of
overidealization and devaluation; and marked shifts from baseline to impulsive
outbursts, anxiety states, or other extreme moods. Prevalence of borderline
personality disorder is estimated to be about 2% of the general population, 10%
of those seen in outpatient mental health clinics, and 20% of psychiatric
inpatients. Although it was previously reported that women constitute about 75%
of those with the diagnosis (84), more recent studies indicate no differences by
gender (85). An estimated 57.4% of persons with borderline personality disorder
meet criteria for an SUD, and multiple studies confirm that significant
percentage are women (86).
Initial formulations and discussion of borderline personality disorder
emerged from the psychoanalytic tradition and downplayed the possibility that
abuse experiences were real, in favor of the view that fantasy distortion, strong
impulses in a weak ego structure, maternal conflicts, and separation and loss
experiences were decisive. The possibility that fearfulness, anger, and suspicion
of the borderline patient might have its roots in real childhood trauma was
minimized (87). Cultural denial of childhood abuse was pervasive until the
attention to PTSD created a knowledge base that revised earlier notions about
abuse as mere fantasy (88,89). Herman, van der Kolk, and others have explored
the possibility that actual traumatic experiences play a key role in the etiology of
borderline pathology. Subsequently, a literature has emerged that described a
relationship between borderline pathology and childhood physical and sexual
abuse. Although childhood trauma is not a necessary cause for borderline
personality disorder, it can be a sufficient contributing factor (90–93). A history
of CSA and a family history of SUD are associated with longer time to clinical
improvement of borderline personality disorder (94).
In summary, the prevalence of co-occurring disorders in women underlines
the importance of offering psychiatric services well integrated into outpatient
and residential (nonmedical) treatment services. Many barriers persist except for
those with severe mental illness, and resources for this population are often
inadequate. In addition to education about addiction, providers should include
material on co-occurring mental disorders and how they can influence relapse
and recovery. This education should have many of the same components as
substance use topics: (a) nature of the disorders commonly found in women;
their usual course and prognosis; (b) important factors such as genetics,
environmental stressors, and traumatic experiences; (c) misunderstandings about
medication; (d) relapse warning signs; and (e) how to maximize recovery
potential. Patients benefit from clarification of what constitutes effective
teamwork with the physician (log of symptoms, notes about MD
recommendations, when to call and when to wait, etc.)
SPECIAL POPULATIONS
Immigrants: Gender roles vary greatly, especially among immigrant groups, in
which the degree of acculturation determines many of the constraints on the
woman’s role. Use of alcohol and other drugs may be taboo for women, so
recognition of their use, or seeking treatment for problems related to use, may be
impossible. Those from patriarchal cultures can face strong taboos about
disclosing family secrets, especially around interpersonal violence. Women can
fear abandonment once they violate cultural norms. Those disclosing sexual
violations can risk severe devaluation within, or expulsion from, their
community, and they can lack the hope for improvement that could propel them
past this barrier. Many fear institutions such as the police, social services, and
mental health agencies that might provide alternative resources (95,96).
Culturally sensitive and specific education and prevention messages have begun
to be developed for women in some subgroups, but much more work in this area
remains to be done.
Lesbians are at particular risk because extensive use of alcohol and drugs is
often part of the culture (97). Socializing patterns built around bars and drug
sharing increase the risk of addiction but do not necessarily lead to recognition
of the attendant problems. These women generally are more dependent on
lesbian friendship networks than on families or marital bonds, and it is important
not to pathologize their adaptive system of mutual reliance as “codependence.”
Historically, lesbian bars were seen as gathering places and safe arenas for self-
expression and, in many areas, they still are the only place where such behavior
can occur. A study of college undergraduates confirms increased use of alcohol,
tobacco, and other drugs among sexual minority women, with bisexual women
having the highest use (98). Even when problems are recognized, women may
avoid treatment agencies if they fear discrimination or lack of understanding
about their specific needs (99). However, data suggest that lesbian and bisexual
women, with and without psychiatric disorders, are quite successful in accessing
treatment (100).
According to 2017 estimates, there are approximately 1 million transgender
persons in the United States, and they are considered a highly vulnerable
population (101). Many of the studies focus on the high rates of HIV in this
population, but substance abuse rates also elevated (102,103). Among the
contributing factors are family rejection, lack of social support, stigma, and
minority stress (104). A lack of NIH-funded research on illicit drug use in the
LGBT populations (105) contributes to gaps in knowledge, particularly in the
area of effective treatment interventions. There is a scarcity of well-designed,
culturally sensitive research on treatment interventions for transgender women.
The Minority Stress Model suggests that clinicians should focus on promoting a
positive identification of the transgender community while addressing issues
such as transphobia, discrimination, and lack of social support that elevates
health risks for this group (106).
TREATMENT ISSUES
In a review of 280 articles published between 1975 and 2005, and in a recent
review chapter, Greenfield and her colleagues examined substance abuse
treatment entry, retention, and outcomes in women (19,107). Most studies report
a higher ratio of men to women entering treatment, on average, 3:1. Population
studies report a smaller gender gap, but this may be in part because of women’s
tendency to seek help in medical or mental health settings (108,109). Barriers
vary but include lack of pregnancy services, lack of child care, fears of loss of
custody or of prosecution, and inadequate services for women with co-occurring
disorders. With respect to treatment retention, Greenfield and colleagues
conclude that larger studies suggest gender is not a significant predictor of
outcomes overall, but specific treatment elements improve outcomes for various
subgroups. For example, inclusion of children enhances engagement and
retention for women seeking residential treatment or intensive day treatment.
Some of these key issues are explored further below.
Management and Retention Issues

The finding that women have high rates of three or more disorders has
consequences for treatment. New work on readiness to change shows promise
for improving women’s treatment. Brown and colleagues (110) noted that
candidates for addiction treatment can vary in their commitment to make
changes in a variety of areas that will affect their prospects. They have
developed a Steps of Change Model that covers four areas in which changes may
be relevant: (a) domestic violence, (b) risky sexual behaviors, (c) addictive
disorder behaviors, and (d) emotional problems. Their work supports the
hypothesis that the most immediate or threatening problems will be what a
woman focuses on first, and she selects her treatment modality accordingly.
Women with substance use disorder who are in domestic violence situations are
relatively resistant extricating themselves and also to addressing their alcohol
and drug use. Once they make the decision to move, they are preoccupied with
achieving greater safety and keeping or maintaining access to their children and
see their alcohol and other drug problems as secondary. By contrast, women with
other mental health problems are more receptive to treatment for their substance
use disorder. Treatment providers need to be willing to start by addressing those
problems the woman is most ready to change while cultivating readiness in other
areas identified by the clinician as important for long-term success.
The number and severity of problems experienced by women can be
translated into a measure of level of burden. In studies of patients with a high
burden, such women tend to be at greatest risk of early termination and poor
outcomes even when they do remain in treatment for longer periods of time (60).
Integrated treatment for multiple disorders thus is especially important in
designing or selecting a treatment program to meet women’s needs. It generally
is agreed by providers that women-only programs or activities are an important
aspect of effective treatment. Current research on this question does not yield
definitive findings and many important questions remain to be carefully
explored. An examination of the services offered in women-only programs
compared with mixed-gender programs in southern California found that the
most consistent difference was the provision of services specific to women’s
needs, particularly those associated with pregnancy and parenting (111). These
services included parenting classes, children’s activities, and pediatric, prenatal,
and postpartum services. Women-only programs also were more likely to assist
with housing, transportation, job training, and practical skills training. Thus,
even though programs can present themselves as doing individualized treatment
planning, women-only programs appear to be better equipped to meet women’s
needs. These programs also were more likely to be funded through the Medicaid
system instead of fees or private insurance, reflecting the lower socioeconomic
status of their client population. Indeed, Greenfield and colleagues report that
women in general are more dependent on public insurance for treatment (19).
Medical Coordination
It is especially important that residential and outpatient programs without such
care on site develop methods or liaisons for effective case management.
Addiction medicine specialists can help such programs develop protocols and
procedures to ensure that the counseling staff members review a woman’s
medical status and are clear in their role as facilitators of integrated services.
Larger programs have found that a “medical coordinator” who functions as a
medical case manager can provide more systematic attention for medical
concerns.
Child Reunification
Retention in treatment and provision of specific services appear to be predictors
of child reunification. A large-scale study of 1115 mothers and their children
documented that mothers treated in programs with a high level of family-related,
education, or employment services were approximately twice as likely to be
reunified with their children. A high-risk group of mothers with employment and
psychiatric problems were less likely to be reunified with their children;
however, completion of 90 or more days in treatment approximately doubled
their rates of reunification (112).
Treatment Outcomes
A prospective longitudinal study examining service needs, utilization, and
outcomes in women-only and mixed-gender programs found that those in
women-only programs had greater problem severity but better outcomes in the
areas of drug use and legal problems (113). This study had a large, ethnically
diverse sample of women in community-based treatment in eight different
programs in California. The 189 women in women-only programs tended to be
in residential treatment, while the 871 women in mixed-gender programs were in
outpatient treatment. Those in women-only programs had greater addiction
severity index severity scores in the areas of alcohol, drug, family, medical, and
psychiatric domains.
In a series of trials, Greenfield and colleagues (114,115) compared a manual-
based 12-session Women’s Recovery Group (WRG) and a mixed-gender Group
Drug Counseling (GDC). Both groups reduced drug use while in treatment, but
the WRG demonstrated significant improvement in reducing alcohol and other
drug use during the 6-month and posttreatment phase. Although both groups
were satisfied with their treatment, women were significantly more satisfied with
WRG. The WRG demonstrated comparable effectiveness to standard mixed-
gender treatment (ie, GDC) and is feasibly delivered in an open-group format
typical of community treatment. Based on her research, Dr. Greenfield has
provided a comprehensive manual for clinicians conducting WRGs (116). This is
a significant contribution to women’s treatment.
It appears that gender-specific treatment is also associated with higher rates
of continuing care. In a quasi-experimental retrospective study of women and
children in residential treatment, those in specialized, women-only programs
who completed the residential phase were more likely to continue appropriate
care than those in mixed-gender programs (117).
Aside from the different needs and characteristics of male and female
substance abusers, there is reason to think that women-only groups tend to foster
greater interaction, emotional and behavioral expression, and more variability in
style than mixed-gender groups. Women in mixed groups tend to engage in a
more restricted type of behavior, whereas the behavior of the men shows a wider
variability (118).
A study that recruited and followed 259 women continues the mixed picture
about effectiveness of single-gender treatment. Those in women-only treatment
reported significantly less substance abuse and criminal activity, but there were
no differences in arrest or employment status at follow-up (119).
It is currently not known whether these differences are most influenced by
the overall characteristics of the women-only treatment setting or by specific
services provided by these programs. As McLellan and colleagues have shown,
the tightness of fit between the individual’s problem profile and the actual
services received are more relevant than the specific treatment setting (120,121).
It is also possible that women-only programs create a distinctive type of synergy
that makes it difficult to disentangle the active ingredients. Veterans and
members of sexual or ethnic minorities are often enthusiastic about homogenous
groups, though research has not focused on whether there is greater
effectiveness.
Physical and Sexual Abuse and Domestic

Violence
Although more than a third of women with PTSD fail to recover after many
years, even with professional treatment, the average duration of symptoms was
shorter among women in treatment (49), suggesting that existing treatments did
confer some benefit. Co-occurring psychopathology typically is associated with
less-favorable addiction treatment outcomes. However, in a study by Gil-Rivas,
Fiorentine, et al. (56), abused clients were more likely than their nonabused
counterparts to participate in counseling and just as likely to complete treatment
and remain drug-free during and up to 6 months after treatment.
Parenting and Attachment

Trauma-related difficulties can impair parenting in a variety of ways (62).
Women with histories of childhood trauma can have attachment problems that
impact their own parenting, particularly their ability to nurture. They often lack
appropriate role models, leading to reliance on physical punishment, difficulties
setting appropriate boundaries, and neglect. They may be unable to integrate
protective discipline and affection. Women with sexual abuse histories may be
deeply mistrustful of men but at the same time miss danger signs that their
children are at risk. Obviously, current alcohol and other drug use will
exacerbate these vulnerabilities. It is important to keep in mind that not all
women with histories of abuse will abuse their children. Clinicians should be
observant but avoid conveying a pessimistic attitude toward a woman’s
prospects for being a good parent.
Trauma-Informed Systems
Currently, efforts are underway to modify service systems to meet the needs of
clients with histories of abuse and violence. At minimum, these systems need to
be trauma informed or knowledgeable about and sensitive to trauma-related
issues present in survivors. Most importantly, these services will be delivered in
a way that avoids retraumatization and encourages patient participation in
treatment. Trauma-specific services include appropriate assessment methods and
specific interventions to address trauma issues (122). Parenting classes offered to
women should be trauma informed.
Seeking Safety (123–125) is a well-accepted and widely disseminated
trauma-specific treatment intervention for those with substance abuse and a
trauma history. It is an early-stage intervention designed to stabilize the patient
(create safety) with respect to both substance abuse and PTSD, integrated within
a manualized but flexible treatment approach. It has been unusually well
accepted by clinical staff and clients alike. Najavits has been developing a
manual and other materials for the second stage, Creating Change, which
focuses on processing trauma issues and forming a new identity (see
www.seekingsafety.org).
Preschool children are more vulnerable to the effects of domestic violence
(126) than older children. It has been noted that children with battered mothers
experience posttraumatic stress reactions themselves. These children often are
subjected to ongoing marital conflict, family dysfunction, dislocations and
relocations of home, lack of parental care, economic and social disadvantage,
and interactions with the police and court.
The extensive variety and complexity of children’s reactions to domestic
violence argue for routine assessment and case management for these families.
Partnerships between substance abuse treatment programs and organizations
focused on children can be excellent ways of bringing specialized services to
augment what can be provided in-house. Children can develop a variety of other
problems in response to traumatic events, including thought suppression, sleep
problems, exaggerated startle responses, developmental regressions, deliberate
avoidances, panic, irritability, psychophysiological disturbances, hypervigilance,
and fear of recurrence. Children can engage in repetitive play in which the
trauma is re-enacted, cope by psychic numbing and withdrawal, show
uncharacteristic behavior patterns, and/or become fearful of mundane things.
Cognitive and emotional problems include a preoccupation with physical
aggression, withdrawal and suicidal ideation, anxiety, depression, and social
withdrawal. Behavioral problems include conduct problems, hyperactivity,
diminished social competence, school problems, bullying, truancy, clinging
behaviors, and speech disorders. Physical symptoms include bed-wetting, sleep
disturbances, headaches, gastrointestinal problems, and failure to thrive (126).
Women’s programs are encouraged to utilize public funding available to address
the needs of at-risk children and integrate their services into adult treatment
programs.
Treatment Culture
Women and treatment providers have noted that the male-dominated treatment
culture characteristic of some programs (particularly many therapeutic
communities and veterans’ programs) is not conducive to meeting women’s
needs (127). They stress the importance of a more supportive and less
confrontational approach to treatment. In addition to the gender imbalance in the
client population, reliance on aggressive confrontation contributed to premature
dropout and a treatment environment that can be experienced as disrespectful at
best and frankly abusive at worst. An emphasis on harsh confrontation is
particularly problematic for populations with a high frequency of traumatic
experiences. Treatment methods that exacerbate a woman’s sense of
powerlessness discourage her from revealing and exploring key issues. In
addition, women with severe psychiatric disorders can decompensate and leave
treatment if confrontation is too intense. Reducing the emphasis on confrontation
and broadening the skill base of clinicians has proved a difficult task in some
treatment modalities, particularly those that rely primarily on staff members
without advanced professional training. Although these practitioners may have
extensive training and many have acquired addiction credentials, the style of
intervention they learned first can be difficult to change, particularly if it
involves charismatic or dogmatic personal role models of recovery.
Both the National Institute on Drug Abuse (NIDA) and the Center for
Substance Abuse Treatment (CSAT) have funded specialized research and
treatment demonstration programs focused on women, and these programs have
enhanced the development of provider groups committed to improving women’s
treatment. Additional resources made available through CSAT’s Addiction
Technology Transfer Centers (ATTCs) made it easier to broaden the skill base of
frontline practitioners working with an indigent population. There appears to be
less coordinated activity focused on women in treatment facilities that serve the
insured population. Provider groups serving women also emphasize the
importance of female leadership at all levels of the organization to serve as role
models and to avoid perpetuating the view that major decision-making influence
is reserved for men. Some programs hire only female staff members to facilitate
the task of dealing with sensitive issues such as incest, rape, and battering. This
eliminates the potential benefits of positive male interactions for the women and
their children when included in the treatment. Male staff members in a
residential program are in a difficult position and must have clear boundaries and
a supervision structure that protects them and the patients from potential
boundary violations. This situation also is an issue for female staff members,
particularly in areas with a large lesbian population, since boundary violations
among women usually are more taboo to reveal.
Opioid-Addicted Pregnant Women

It is especially important to reduce early treatment dropout in pregnant women
because participation in treatment is associated with better maternal and neonatal
outcomes. Drug craving and withdrawal were important precipitants of relapse,
especially for individuals using heroin who did not receive medication assisted
treatment (128).
Methadone
Methadone maintenance is considered the gold standard treatment for opioid-
dependent pregnant women (129,130), although there is a growing literature
about the use of buprenorphine. It is important that the dose is adequate in the
context of metabolic alterations in pregnancy. Contrary to common expectations,
higher doses are not associated with increased risks of neonatal abstinence
syndrome (NAS). Although single daily dosing is the most common, a protocol
that increased methadone dose and dose frequency in response to maternal
reports of withdrawal is associated with lower severity of NAS (131). Despite
the fact that some of the women were on relatively high doses of methadone (up
to 180 mg/d), levels in breast milk were small and no adverse events were
detected (132). Women should not be discouraged from breastfeeding if they are
not using illicit drugs and do not have specific contraindications (132,133).
Stereotypes about methadone being “just another addiction” can have prejudicial
influence on medical decisions. The American College of Obstetricians and
Gynecologists considers methadone maintenance the standard of care, but
buprenorphine can be considered (133).
Buprenorphine
Buprenorphine and methadone are category C medications during pregnancy.
This allows a risk–benefit clinical decision to start or continue to treat pregnant
patients with buprenorphine when methadone treatment is not an option or is not
acceptable to the patient. A large-scale, multisite study (the MOTHER study) to
evaluate safety and efficacy of buprenorphine in pregnancy found that compared
to methadone, outcomes were largely similar but the newborns of buprenorphine
patients had lower severity of neonatal abstinence symptoms, thus requiring less
medication and less time in the hospital (134). However, the retention rates of
the methadone-maintained mothers were significantly better than the
buprenorphine group (33% vs. 18%) and the careful, hospital-based induction
required by the research study may make it difficult to implement in the
community.
Inasmuch as women on buprenorphine may become pregnant or may prefer
buprenorphine to methadone, the MOTHER project sought to develop guidelines
based on risk–benefit ratios. It is important to use buprenorphine alone rather
than the buprenorphine/naloxone combination to avoid any risk of prenatal
exposure to naloxone.
Transferring a patient receiving methadone to buprenorphine is challenging
because of the need for the mother to remain off methadone for a protracted
period of time prior to buprenorphine induction and due to the risk of a
precipitated withdrawal. There is currently no medication transition procedure
that avoids these risks, and the associated risks of fetal distress, miscarriage, and
stillbirth. In research studies, this transition has been accomplished using
intravenous morphine in a hospital (135), but this is not a practical option for
community treatment providers. Buprenorphine may also pose complications for
pain management during labor and delivery. The same features that produce an
enhanced safety profile for buprenorphine may mean that pain medications fail
to reach the target receptors. Buprenorphine and methadone in pregnancy are
covered in more detail elsewhere in this volume.
In summary, although methadone is the treatment of choice for pregnant
women with opioid use disorder, the use of mono-buprenorphine is an emerging
option with potential to expand treatment access in rural areas and in other
circumstances where methadone is not available.
Women and the Criminal Justice System

Women constitute the fastest-growing segment of the criminal justice population
nationally and yet have the fewest appropriate social services available to them
(136,137). Women today are more likely than men to serve time in jail or prison
for drug offenses (138). Between 1982 and 1991, the number of women arrested
for drug offenses increased 89% (136). Since 1991, increasing numbers of
women have been incarcerated for crimes committed in the service of drug use.
Half the women reported committing their crimes while under the influence of
drugs or alcohol, and about 40% reported using drugs daily before arrest. Fifty-
three percent of the women in federal prison were unemployed at the time of
arrest (138).
Typically, incarcerated women report that they started using drugs at an early
age. These women commonly were confronted with obstacles such as absent
parents, educational setbacks, parenthood, poverty, drug accessibility, and
minimal social resources. Most came from communities in which crime was
rampant. Additionally, most were victims of childhood sexual and/or physical
abuse, as well as traumatic experiences as adults. Consequently, they had high
rates of depressive and other psychiatric disorders (139). They often suffered
from low self-esteem, depression, addiction, and shame.
Insufficient job skills as a result of poor education undermine self-esteem in
incarcerated women. Low income or poverty results in desperation, thus making
illegal activities more acceptable, especially in the service of drug use. Major
child-rearing responsibilities with inadequate social support systems contribute
to the development of psychiatric disorders in mothers and behavior problems in
children (139). Thirty-four percent of the women in US prisons report being
sexually abused, and another 34% report being physically abused (138).
Women’s social status and gender roles affect sexual risk behaviors and the
ability to take steps to reduce the risk of HIV infection (44), contributing to the
high incidence of HIV in drug-using and incarcerated women. A subsequent
study of 3315 subjects found rates of 7.5% in incarcerated women, several times
higher than found in community samples (140).
Intergenerational and familial transmission of drug use and associated
criminality makes the obstacles confronting these women more debilitating.
National data on women in prison show that 40% of the women reported that an
immediate family member also was in jail (138). In California, 59% of inmate
women reported that family members were currently incarcerated (141). One-
third of the inmates reported that a parent or guardian had abused drugs or
alcohol. For these and other complex and interwoven factors, it is necessary to
intervene decisively in prison prerelease programs to break the cycle of drug use
and criminality and to include family members in the treatment experience
whenever possible. Various states have invested in treatment in custody and
post-release, but many challenges remain to be surmounted (such as a trained
workforce of adequate size), and the data currently support only modest benefits.
However, a recent quasi-experimental study of 2726 women indicated that they
did better for psychiatric, trauma, and substance use outcomes with integrated
treatment and mandated treatment (142).
Prison-based treatment is growing rapidly, and specialized programs for
women are included in this development (143). A 2016 meta-analysis of gender-
neutral compared to gender-informed approaches indicated that women and
girls, especially those with trauma histories, are more likely to respond well to
gender-informed treatment (144).
Both research and clinical experience indicate that community-based
services after treatment in prison significantly increase the percentage of
offenders who remain drug-free 18 months after release. Thus, programs in large
states such as California emphasize the importance of a seamless transition to
services in the community and provide substantial funding to accomplish these
goals (145). Although the implementation remains imperfect, segments of the
criminal justice system are increasing their understanding of what it takes to
achieve and maintain positive outcomes. Drug courts and diversion initiatives
such as California’s Proposition 36 (treatment rather than incarceration) have
also shown success in reducing recidivism, likely in proportion to their access to
psychiatric and social services.
CONCLUSIONS
Although gender differences have been well studied in specific areas, there are
many gaps in our understanding. Biomedical effects are far better understood for
alcohol than for the illicit drugs. Research and treatment funding incentives over
the past 25 years have provided a much better understanding of women’s
treatment needs and preferences, but much work on implementation needs to be
done. Removing obvious treatment barriers, such as transportation and child
care, increases women’s participation in treatment. Treatment for women must
be comprehensive, including their spouses, partners, and children. Research is
needed to determine how best to intervene with children to reduce the negative
effects of their parents’ substance use disorder. Programs need to be capable of
addressing co-occurring mood and anxiety disorders, particularly PTSD and
eating disorders. When queried, women report that women-only groups and
other activities and role models at all levels of decision-making in the
organization are important to them. Advocacy is still needed for research to
clarify which gender-specific treatment components are most influential in
improving outcomes.
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CHAPTER 39
Traumatic Brain Injury and Substance
Use Disorders
David L Pennington, Tatjana Novakovic-Agopian, and
Steven L. Batki
CHAPTER OUTLINE
Introduction
Definition of Traumatic Brain Injury
Epidemiology of TBI
Prevalence of SUD and TBI
Risk Factors Influencing Co-occurrence
Harms Associated with Co-occurrence of SUD and TBI
Assessment of Co-occurring TBI and SUD
Factors Influencing Recovery From TBI
Treatment Approaches for TBI and SUD
Conclusions
INTRODUCTION
Traumatic brain injury (TBI) is a major cause of death and disability in the
United States. In 2010, the Centers for Disease Control and Prevention (CDC)
estimated that TBIs accounted for ~2.5 million hospital emergency department
(ED) visits in the United States. Among TBIs that occurred in community
settings in the United States, falls accounted for 41% of TBIs (disproportionately
affecting the youngest and oldest age groups), followed by blunt trauma (16%)
and motor vehicle accidents (14%). Direct costs for TBI hospital care, extended
care, and other medical care and services, coupled with indirect costs such as
lost productivity, were estimated by the CDC to be $76.5 billion annually (1,2).
These numbers likely underestimate the occurrence and associated cost of TBIs
since they do not account for those who did not receive medical care in ED,
those who had only outpatient medical care or those who received care at a
federal facility, such as a US military hospital or a Veterans Affairs hospital (3).
Those who serve in the military are at significant risk for TBI. Between 2000
and 2017, the U.S. Department of Defense (DOD) data indicate that 379,519
service members were diagnosed with a TBI. Internationally, continuing
conflicts have increased the likelihood of exposure to high-energy blasts and
explosions. As a result of this increasingly common mechanism of injury, more
service members wounded in war are returning with multiple complex injuries
including TBI, spinal cord injuries, eye injuries, musculoskeletal injuries, and
mental health problems. The term “polytrauma” has been introduced to
encompass injuries to more than one physical region or organ system that result
in physical, cognitive, psychological, or psychosocial impairments and
functional disability. Mental health comorbidities are common in this patient
population including posttraumatic stress disorder (PTSD), depression, anxiety,
and substance use disorders (SUDs).
There is a growing body of literature indicating that as many as 60% of
persons with TBI have significant problems with alcohol and/or other substances
(4–7). The relationship between TBI and SUDs is bidirectional, with evidence
for higher rates of TBI in individuals with preexisting SUD and also higher rates
of SUD in individuals following a TBI. Although it is well demonstrated that
TBI is a common co-occurrence with alcohol and SUD (8), little is known, and
even less is disseminated, regarding prevalence, associated harms, or treatment
strategies for patients with both TBI and unhealthy substance use. Knowing
about TBI and the clinical strategies required to address it appropriately is a
needed skill set for addiction medicine professionals.
This chapter defines and classifies TBI, discusses the prevalence and
neurobehavioral harms related to TBI and alcohol and other substance use, and
provides an overview of assessment aimed at identifying symptoms during
acute-stage injury. We also discuss potential cognitive and pharmacotherapy
treatment approaches for patients with TBI and unhealthy alcohol use.
Recommendations for early screening and assessment of TBI and substance use
are highlighted.
DEFINITION OF TRAUMATIC BRAIN

INJURY
A TBI is an injury that disrupts the normal function of the brain. It can be caused
by a hit, explosive blast, jolt to the head, or a penetrating injury (9). The DOD
and Department of Veterans Affairs (VA) (10) have defined TBI as any
traumatically induced injury and/or physiological disruption of brain function
that involves new onset or worsening of at least one of the following clinical
signs, immediately following the event:
1. Any period of loss of or a decreased level of consciousness

2. Any loss of memory for events immediately before or after the injury
3. Any alteration in mental state at the time of the injury (eg, confusion,
disorientation, slowed thinking)
4. Neurological deficits (eg, balance disturbance, change in vision, other
sensory alterations, aphasia.) that may or may not be transient
5. Intracranial lesion secondary to head trauma (excluding other acquired
conditions, eg, stroke, tumor, etc.)
Classification
TBIs are heterogeneous, and there are several ways to categorize patients in
terms of clinical severity, mechanism of injury, and pathophysiology. Mild TBIs
(synonymous with concussions) are the most frequent TBIs, accounting for
70%-90% of all brain injuries treated in hospitals with incidence likely
>600/100,000 (11). Regardless of injury mechanism, TBI severity grade at the
time of the injury (mild, moderate, or severe) is determined by using four
indices:
Glasgow Coma Scale (GCS)—The GCS is a 15-point scale based upon

ratings of the patient’s best motor, eye opening, and verbal responses
following an injury.
Length of coma (LOC) (duration of unconsciousness)—Coma or
unconsciousness is the time a patient is nonresponsive after injury.
Length of period of altered consciousness or mental status—Following a
TBI, an individual may be conscious but may nonetheless be confused,
disoriented, feel dazed, have difficulty tracking events, and may respond in
a confused manner to questions.
Length of posttraumatic amnesia (PTA)—PTA is the time interval from
when the person regains consciousness until he or she is able to consistently
form memories for ongoing events (12). Of note, PTA can be influenced by
medications that are given in routine trauma care (ie, pain medication).
The classification provided in the following table has been accepted by DOD/VA
and the American College of Rehabilitation Medicine (ACRM) (13) (Table 39-
1).
TABLE 39-1 Classification of TBI

DoD/DVA/ACRM consensus-based classification of TBI Severity.
Diagnosis of TBI
In cases of moderate or severe TBI, the diagnosis is readily assessed through
history and examination in the emergency medical setting. TBI diagnosis may be
complicated in cases of closed head injury accompanied by other life-threatening
injury, particularly in the case of mild TBI (mTBI). In such cases, mTBI might
not be diagnosed until days to weeks following the injury, when neurobehavioral
problems are noticed, and sometimes only after other emergent medical
problems are resolved. Such patients may require detailed neurological exam,
brain imaging, and/or formal neurocognitive evaluation by a neuropsychologist
to establish the presence and associated symptoms of a TBI.
Acute-stage injury parameters of LOC, PTA, and GCS are strongly
predictive of long-term recovery and form the basis for establishing a diagnosis
of TBI (14). Other TBI symptoms may be physical (eg, fatigue, headache,
vertigo, dizziness, or disordered sleep), cognitive (eg, deficits in attention or
memory), or emotional (depression, anxiety, affective lability, apathy, or other
changes in personality), commonly referred to as postconcussional disorder (15)
or “postconcussion syndrome” (PCS) (16). Although these symptoms can be
used to support an mTBI diagnosis, this should only be done to the extent that
these symptoms cannot be accounted for by causes other than mTBI itself such
as psychological reaction to physical or emotional stress (14). The frequent
psychological trauma that can accompany head injuries may also make it
difficult to accurately determine the degree of altered mental status and
complicates assessment of causality for symptoms. In sum, behavioral,
cognitive, and emotional symptoms can be nonspecific and therefore must not be
used in isolation to establish a TBI diagnosis.
Military Populations: Diagnosis of mTBI in military populations is even
more complex due to reluctance to report brain injuries for fear of removal from
duty, delays between time of TBI and discharge from military service, and
because of the unique mechanisms of injury, often including repeated exposure
to blasts. It is estimated that 50%-80% of battlefield injuries in US veterans are
now due to blast exposure (17,18). Worldwide, blast-induced traumatic brain
injury (bTBI) is considered the “signature wound” of modern warfare (19).
Primary blast injury refers to injury that is caused by exposure to a blast wave, a
sudden change in atmospheric pressure (14). This blast wave is thought to
account for unique injury to the brain resulting in behavioral traits similar to
PTSD in humans and biochemical, pathological, and physiological effects on the
nervous system in animal models (20). Primary blast injury is often accompanied
by blunt or penetrating trauma from material propelled by the blast wave
(secondary blast injury), by the body being thrown to the ground or against an
object from the wave (tertiary blast injury), or from other injury mechanisms
attributable to the blast such as burns, wounds, broken bones, or breathing toxic
fumes (quaternary blast injury). All of these injuries may contribute to symptom
development following bTBI and add to the complexity of diagnoses. There are
currently no specific bTBI treatment strategies, but research aimed at
understanding the mechanisms underlying bTBI is steadily growing and will aid
in the development of specific treatment strategies for this type of injury. See
Courtney and Courtney (20) for a review of the potential underlying mechanisms
of primary bTBI.
High-Impact Sports: Repeated exposure to primary mild TBIs have been
associated with the development of a progressive, neurodegenerative disease
called chronic traumatic encephalopathy (CTE). The majority of confirmed CTE
cases have been among athletes competing in high-impact sports, such as
football, boxing, soccer, ice hockey, wrestling, and rugby (21). Symptoms
associated with CTE include disruptions in mood, behavior, cognition, and
motor function. It typically takes 8-10 years after repeated exposures to present
and can range in severity from mild symptoms to those that produce a
parkinsonian-like syndrome (22). Currently, CTE can be diagnosed only via
postmortem examination and can be challenging to diagnose due to its overlap
with other neurodegenerative diseases such as Alzheimer dementia (22). See
Blennow et al. (23) and Safinia et al. (22) for a review of CTE pathology.
Although there are no established clinical criteria or biomarkers that support the
diagnosis of CTE (23), increased attention in the media and medical research has
resulted in more studies that may soon provide a pathway for diagnosing CTE in
living patients, including the use of PET imaging to identify tau-specific ligands
indicative of CTE (22). Ultimately, prevention may prove to be the most
beneficial approach to reducing CTE. Prevention methods include the use of
optimal helmets with adequate shock absorption, modifications to rules in high-
impact sports, and the use of more sensitive neurobehavioral assessment tools
and routine cognitive testing (22).
Assessment: Civilian-related mTBI can be assessed using the Ohio State
University TBI Identification Method (24,25), a structured interview, which
allows for breadth of assessment (number and severity of TBIs, age of onset, and
duration of symptoms). The Boston Assessment of Traumatic Brain Injury-
Lifetime (BAT-L) (26) is also a retrospective tool used to characterize and
diagnose lifetime TBI. The BAT-L is unique in that it guides the examiner to
distinguish between physiological disruption of consciousness and the
psychological response to co-occurring traumatic events. The BAT-L also
includes assessment of blast injury common to veterans.
To date, the diagnosis of mTBI in veterans returning to the United States
relies on data acquired from self-report through the use of a limited set of
validated semistructured interviews. The VA TBI Identification Clinical
Interview (27), the Warrior-Administered Retrospective Casualty Assessment
Tool (WARCAT) (28), and the Structured Interview for TBI Diagnosis (29) are
structured clinical interviews, which focus on military-related head injury and
can be administered postdeployment.
The most widely researched and used tool for assessment of concussion
(mTBI) in athletes is the Sports Concussion Assessment Tool-V3 (SCAT-3) (30).
The SCAT-3 combines the GCS, Maddocks score (a set of orientation questions,
eg, at what venue are we today, which half is it now, who scored last in the
match, did your team win the last game), symptom checklist, a standardized
assessment of concussion (31), and the balance error scoring system (32).
Although this is a well-validated assessment for sports injury–related
concussion, it has been developed to assess a younger, healthier, and more
homogenous cohort, not the general civilian or military population (33).
All of the abovementioned tools assess for GCS, LOC, and AOS in relation
to a type of trauma (eg, blunt, fall, motor vehicle accident, etc.). Some include
the acquisition of information related to blast injury, and the SCAT-3 is specific
to sports-related injury. Although all these instruments possess some degree of
validity in assessing mTBI, there is a need for cross-validation of their accuracy
to assess mTBI in patients with SUD and across the lifetime.
EPIDEMIOLOGY OF TBI
Approximately 80% of patients who sustain TBIs have had a mild case (3).
Individuals with uncomplicated mTBI/concussion typically recover fully within
the first 3 months (34). However, about 10%-15% continue to report symptoms
for months (35,36) or years postinjury (37,38). Individuals with repeated mTBI
have an increased risk for persistent symptoms.
Persisting functional limitations are also common in patients with moderate
to severe TBI. At 1-year follow-up, functional limitations were found in up to
47% of patients discharged from acute care hospitals after experiencing TBI
(39). In another sample of persons hospitalized with moderate or severe TBI
(40), 24% had failed to return to work at 1-year follow-up. Similarly, in a 15-
year follow-up study of a cohort of US veterans from the war in Vietnam, only
56% of those with TBI were employed compared with 82% of the uninjured
controls (41).
PREVALENCE OF SUD AND TBI

Literature addressing illicit substance use at the time of head injury is limited.
Currently, there is no standard for assessment or reporting of substance use for
patients presenting with TBI. Thus, rates of substance use at time of injury
remain largely unknown; however, it is known that alcohol intoxication at the
time of a TBI is common (8). Studies indicating alcohol use at the time of injury
range from as low as 37% to as high as 50% of all cases (42–47). Rates of
preinjury nonalcohol SUDs range from 21% to 40% and preinjury alcohol use
disorders (AUDs) range from 44% to 79% (48–52). Likewise, studies examining
preinjury AUD and SUD suffer from a lack of uniformity in assessment methods
and diagnostic criteria limiting their interpretability. Overall, current rates of
SUD in patients with TBI are estimated to range up to 50% (8) but should be
considered with caution given the methodological limitations.
Regarding military populations, US military service members with a hospital
diagnosis of TBI are 2.6-5.4 times more likely to be discharged from the military
for alcohol or drug use when compared to the total discharged population (53).
The prevalence of SUD and unhealthy alcohol use is approximately twice
greater in veterans with TBI than in those without. There is a 26% rate of
substance-related disorders in US veterans with a positive TBI screen compared
to 9.7% in those with a negative screen (risk ratio of 2.27) (6). In a study of over
300,000 Operation Enduring Freedom and Operation Iraqi Freedom veterans,
the rate of SUD diagnoses in veterans with TBI was more than twice that of
veterans without TBI (22% vs. 8%) (7). A TBI also increases service members’
risk of being diagnosed with AUD in the 12 months following head injury by
50% (54).
Rates of head injury in populations with SUD range from 31% to as high as
68% (55–58). Studies examining TBI in population with SUD have similar
methodological problems to studies examining rates of SUD in populations with
TBI. Most reports of head injury in populations with SUD are retrospective, lack
specificity in regard to severity of head injury, and rely on self-report methods
for the documentation of a head injury. These reports often loosely define TBI as
any head injury with loss of consciousness, and samples consist primarily of
those seeking treatment for SUD. Although the research in prevalence rates of
TBI and SUD have methodological limitations, studies consistently find high
correlations between these diagnoses.
RISK FACTORS INFLUENCING CO-

OCCURRENCE
Those with unhealthy substance use are more likely to engage in high-risk
behaviors that result in TBI, that is, motor vehicle accidents, falls, and blunt
trauma from violent acts (5). There is substantial literature demonstrating that
substance use often decline immediately following brain injury but later increase
commensurate with improvement in functional status (5,59). However, not all
subpopulations of patients with TBI and SUD exhibit this immediate drop in
substance use; there is emerging evidence showing that TBI increases the risk of
heavy drinking immediately following TBI in young men with a previous history
of SUD problems and diagnosis of depression (59). At this time, little is known
regarding potential moderating factors of postinjury substance use recovery in
patients with TBI.
TBI Increases Risk of Developing an SUD

There is a growing body of literature showing that TBI alone can result in
increased risk for substance-related problems postinjury (60). Hibbard et al. (50)
reported that patients without a history of DSM-IV Axis I disorders (including
SUD) had increased rates of postinjury SUD relative to community controls.
After controlling for alcohol use prior to injury, Silver et al. (61) also found that
TBI was associated with increased rates of SUD compared with community
controls, evident up to 36 months postinjury (62). Patients with TBI are also
more likely than individuals without TBI to be treated with potentially addictive
medication such as opioids, as has been shown in a study of US veterans of the
Iraq and Afghanistan conflicts (63).
Risk for SUD following TBI may be greater in those with mild to moderate
TBI (64). The increase in alcohol- and drug-related discharges among service
members is specific to those with a history of mild or moderate TBI. Subjects
with severe TBI have not been shown to have increased incidence of substance-
related discharge (53). In fact, less severe functional disability following TBI is
related to worse SUD-related behaviors. Increased rates in substance- and
alcohol-related problems in those with mild to moderate TBI can be partially
attributed to psychiatric comorbid disorders such as depression and PTSD and
physical discomfort of postinjury chronic pain (65). The decreased risk of SUD
among those with a severe TBI is likely due to the inability to seek or access
drugs and alcohol because of the debilitating nature of the head injury. There is
also early evidence showing that this increased SUD risk is related to the
neurobiological and related neurocognitive mechanisms underlying TBI (66–68).
Dopaminergic Neurocircuitry in Animal

Models of TBI
Many of the neurological deficits associated with severe TBI are a result of
direct anatomical damage. However, changes in neurotransmitter systems,
particularly in the long axonal projections of the dopamine pathways (easily
injured by acceleration and deceleration shearing force), appear to be vulnerable
to mild/moderate TBI (66). In animal models, a 25% reduction in dopaminergic
neurons in the substantia nigra can be observed 28 days after injury and is
associated with blood–brain barrier breakdown and microglial activation
accompanying an inflammatory process (68). Dopamine levels rise after TBI in
numerous brain regions, including the medial prefrontal cortex, but are followed
by reductions ~2 weeks following the injury (68). Controlled impacts
administered to the parietal cortex of rats resulted in lower dopaminergic release
after electrical stimulation, decreased dopaminergic clearance, and decreased
dopamine transporter expression in the striatum ipsilateral to injury compared
with naïve animals (67,68). Reduced dopaminergic clearance and release are
thought to be a compensatory mechanism to aid in the maintenance of
extracellular dopamine levels. Reduced dopamine release in the context of
normal or increased synthesizing capacity is likely related to a deficit in
vesicular trafficking, reduction in amount of dopamine per vesicle, or an
alteration in the feedback control of dopamine release (68). Evidence of
disruption of the dopamine system in humans is available but limited. SPECT
and PET imaging studies have demonstrated altered dopamine transporter and
D2 receptor binding varying by region in the striatum (68). TBI severity may be
related to variance in dopaminergic cell loss (68).
Emerging Evidence for Dopaminergic Agonist

Treatment for TBI
Following evidence for dopaminergic changes seen in animal models and
because these changes may also be present in humans, preclinical and clinical
trials have begun to look at dopamine pathway drugs to target
pathophysiological and functional outcomes of TBI. Dopamine is the most
common catecholamine found in the central nervous system and has been the
most studied neurotransmitter target for TBI treatment to date, but it should be
noted that other catecholamines such as epinephrine, norepinephrine, and
monoamine agonists are also being evaluated for TBI intervention (69).
Evidence showing that dopamine agonists improve cellular and functional
deficits associated with TBI is growing. Dopamine agonists used for post TBI
treatment include bromocriptine, amantadine, dopamine agonists used in
Parkinson disease such as ropinirole and pramipexole, stimulants such as
methylphenidate and amphetamine, and dopamine reuptake inhibitors (69).
Preclinical and clinical trials of these medications have been tested to target a
wide range of TBI-related symptoms including impaired cognitive function (eg,
spatial memory, working memory, attention, executive function), impaired motor
deficits, agitation, sleep disorders, depression, and neuroinflammation and to
promote neurogenesis, postinjury plasticity, and synaptogenesis (69).
Neuroprotective and therapeutic dopaminergic targeting strategies have been
beneficial for memory and attention recovery (66). However, the clinical trials
conducted in this line of work have limitations including replication failure, lack
of specificity, lack of examination into moderating characteristics such as genetic
factors, and difficulty translating therapies into clinical practice (69).At this time,
there is insufficient evidence to support medication interventions. If future
medications prove to be efficacious, then they are worth investigating in the
treatment of both AUD/SUD and TBI, given that the clinical target is often
related to self-control processes mediated by executive dysfunction, a key
problem in addiction treatment.
TBI-Related Neurobehavioral Risks of

Developing Addiction
The orbitofrontal cortex (OFC) is a component structure of the prefrontal cortex,
which underlies the reflective, control system implicated in addiction. The OFC
is also especially vulnerable to direct blunt trauma to the head and to shearing
along the sharp edges of the orbital surface of the skull that can occur following
percussive shock waves to the brain (60). TBI structural damage to the OFC can
result in organic personality changes including impaired empathy, increased
problems with interpersonal functioning, antisocial behavior, poor distress
tolerance, apathy, increased mood lability, and hostility (48,60,70–78).
OFC damage is also associated with impulsive responding (79–81). Patients
with TBI have been shown to prefer small immediate rewards over larger
delayed rewards, prolong decision-making, make poor quality of decisions, and
display impulsive responding compared to controls (82–85). Patients with TBI in
comparison to healthy controls have also been shown to have difficultly
discriminating between contingencies and altering behavior based on past
experience, thus not being able to maximize future reward (86).These complex
deficits in decision-making may contribute to difficulties with poor judgment
and inhibition in patients with TBI. Thus, patients with TBI with frontal damage
may be impaired in their ability to delay gratification and seek immediate reward
related to drug and alcohol use. This is similar to behavior typically associated
with abnormalities of the dopamine system found in patients with OFC lesions
(82,87,88). In the OFC, dopamine enables shifting from immediate versus
delayed reward through the processing of salience attribution and in the insula
through interceptive information processing.
In sum, decision-making and risk aversion are dependent on dopamine
signaling in the OFC. Dopamine neurocircuitry in the OFC is disrupted by TBI
in at least a subset of patients; disruption of dopaminergic signaling in the
frontolimbic reward system is thought to bring about addictive behavior (89).
There may be a subset of patients with TBI that have disrupted executive
function, leaving them at risk for development of psychological disorders
including unhealthy substance use following injury. Identifying these patients
and providing treatment aimed at improving executive function may aid in
reducing risk for development or re-emergence of SUDs.
HARMS ASSOCIATED WITH CO-
OCCURRENCE OF SUD AND TBI
Substance use in those with TBI presents an even greater challenge and is
associated with increased risks of adverse medical, neurobehavioral, vocational,
and life satisfaction outcomes.
Mortality
In studies examining predictors of mortality in patients with TBI, excessive
alcohol use is independently predictive of mortality (90,91). Younger age and a
previous history of substance use have also been associated with increased
mortality rates in TBI (48,92,93). For instance, patients with TBI who
demonstrate unhealthy alcohol use had 41% mortality rate compared to
13%-23% for those with no, occasional, or regular alcohol use at 700 days
postinjury (94). Additionally, in comparison to the general population, the risk of
death by suicide has been reported as being four times higher for patients with
TBI with substance use at the time of hospital admission (95).
Violence
There is an increased risk of violent behavior following head injury mediated by
substance and/or AUDs in individuals with TBI compared to the general
population (96). In a large study conducted by Kreutzer et al. (97), moderate to
heavy drinking both pre- and postinjury increased the rates of aggressive
behavior and arrest postinjury, a threefold increase compared to the general
population (97). Individuals who report drug use or drug use in combination
with alcohol are also more likely to have sustained violent injuries than those
who report alcohol use alone or deny any substance use (51). Additionally, the
incidence of fatal brain injuries due to violent acts is increasing (49). Almost
80% of persons with TBIs from violent-related causes had a history of substance
use (49). Alcohol use alone is also associated with violent acts causing TBI. In a
large study on persons who were hospitalized or died due to TBI, 60% of those
with assault-related TBI had positive blood alcohol concentration upon
postinjury testing (44). Positive blood alcohol upon hospital entry is also
associated with longer hospital stays, acute complications (eg, intubation,
pneumonia, respiratory distress, intracranial pressure), and greater incidence of
neurological impairments at discharge (5).
Neurocognitive Performance
Pre-existing alcohol and other SUDs are associated with lower scores on the
GCS, increased brain tissue atrophy, and poorer performance on a variety of
neurocognitive assessments (8). In 129 people who inject drugs, those with
histories of multiple head traumas involving LOC performed worse than both a
control group and a reference group with only a single episode of loss of
consciousness on multiple cognitive domains including working memory (digit
span), fine motor speed (Grooved Pegboard), processing speed (Trail-Making
Test A), and visuospatial ability and memory (Rey Complex Figure Recall) (98).
Of note, group differences were apparent up to 11 years postinjury (98). Higher
blood alcohol levels at time of injury have also been associated with worse
performance on orientation and naming (Neurobehavioral Cognitive Status
Examination, NCSE), auditory–verbal learning (Rey auditory verbal learning
test), and processing speed(Trail-Making Test A) (99) at 30 days postinjury.
Similar relationships were observed in patients tested 31-60 days postinjury on
the verbal memory and similarities subtest of the NCSE (99). Additionally,
patients with a positive urine screen for illicit drug use upon TBI hospital
admission performed significantly worse on WAIS-R Full-Scale IQ and Verbal
IQ Indices than patients with a negative drug and alcohol screen. Finally, in a
retrospective analysis, TBI inpatients with a blood alcohol level at or below the
legal limit and a positive cocaine screen upon hospital admission performed
significantly worse on auditory–verbal learning (Rey auditory verbal learning
test) than those with similar blood alcohol level but negative for cocaine (99). In
sum, both TBI and SUD have discrete and overlapping impact on cognitive
performance.
Life Satisfaction and Vocation

Only 40% of patients with TBI and unhealthy alcohol use have been shown to
return to work postinjury compared to 73% of patients with TBI without
unhealthy alcohol use (5). Similar effects are seen regarding drug use. Patients
with preinjury substance use are eight times less likely to be employed at follow-
up than patients without preinjury substance use (5). Further, patients with
preinjury substance use report lower productivity and life satisfaction 2 years
postinjury (5).
Mood/Affect Impairment
Mood disorders are common consequences of TBI and are related to preinjury
vulnerability, type and extent of brain damage, and levels of family and social
support following head injury (100). Depressive disorders are the most common
mood disorder among patients with TBI and range from 25% to 50% in the first
year postinjury and 26%-64% over the lifetime (100). Major depression is also
frequently associated with anxiety, aggression, and a history of substance-related
problems (100). In a significant number of cases, mood disorders following TBI
become chronic and resistant to treatment, with a negative impact on community
reintegration and quality of life (100).
Chronic Pain
Chronic pain is associated with both TBI and SUD in civilian and military
populations (101). It is often comorbid with a range of chronic mental health
disorders including depression, PTSD, and SUD (101). As of mid-2017,
published studies examining the co-occurrence of pain and mental health
conditions have typically examined one or two conditions (chronic pain and TBI
or chronic pain and SUD) rather than the co-occurrence of all three. Similarly,
there have been no studies that have prospectively examined the risk and
relationship between unhealthy substance use and pain following TBI (65).
Research involving non-opioid treatment for TBI-related chronic pain is also
limited. However, we did find one study providing evidence that the acceptance
of chronic pain can be beneficial for reducing disability and improving quality of
life in veteran patients with unhealthy alcohol use and mTBI (102). Given the
high rate of these co-occurring diagnoses in US veteran populations, the VA and
DOD have developed an evidence-based guideline for the management of opioid
therapy for chronic pain (103). Similarly, the CDC has also issued guidelines and
best practices for prescribing opioids for chronic pain (104).
Summary of TBI and SUD Harms

The co-occurrence of SUD and TBI is common and is associated with worse
psychosocial and medical outcomes, relapse to substance use, and higher rates of
hospitalization (105). A history of preinjury problems with alcohol and/or
substance use is related to greater mortality rates, postinjury emotional and
cognitive problems, chronic pain, less work productivity, greater associations
with crime, and less life satisfaction following TBI. Collaboration among
specialists in pain management, SUD treatment, and neurology is recommended
(106).
ASSESSMENT OF CO-OCCURRING TBI
AND SUD
Within the alcohol literature, there is robust evidence that screening and brief
intervention and referral for treatment (SBIRT) for at-risk alcohol use as part of
general medical care is highly efficacious and results in large reductions in
alcohol use, increased healthcare utilization, fewer motor vehicle accidents, and
large economic savings (107–109). The Substance Abuse and Mental Health
Services Administration (SAMHSA) recommends SBIRT for medical settings
(inpatient, emergency departments, ambulatory, primary and specialty healthcare
settings, and community health clinics) (110). In 1999, the National Institutes of
Health (NIH) made a recommendation for the inclusion of SUD evaluation and
treatment in rehabilitation programs for TBI (111). Beginning in 2006, the
American College of Surgeons required level I and level II trauma centers to
attempt to identify patients with unhealthy alcohol use and level I centers to
provide an intervention for patients with unhealthy alcohol use. Screening
patients with TBI acutely after injury for both the presence of preinjury
substance use and development of new-onset substance use may promote early
detection and facilitate adequate follow-up health care (112).
To date, little is known regarding the efficacy and effectiveness of screening
and brief intervention for SUD in patients with TBI (109). In regard to
screening, few studies have examined and identified appropriate and
standardized screening instruments that adequately assess for substance use in
patients with TBI despite the fact that both diagnoses can share similar impacts
on cognitive function, mood, and disinhibition (8). Research primarily conducted
from a TBI perspective has limitations in that SUD has not been adequately
defined, thus making outcomes difficult to compare and interpret (8).
Future research will need to develop uniformity in assessment, reporting,
and development of alcohol and substance use screening tools specific for TBI
populations (8). Until such tools are developed, we recommend that clinicians
continue to use standard tools used in general medical and surgical settings.
These instruments include the Brief Michigan Alcoholism Screening Test
(MAST), Substance Abuse Subtle Screening Inventory, and Alcohol Use
Disorders Identification Test (AUDIT) (8,113).
Just as investigators conducting research from a TBI perspective have
inadequately defined and assessed SUD, investigators who study SUD have
made similar omissions in not adequately assessing the specific symptoms and
severity needed to establish TBI (8). Such mistakes include the reliance on a
singular self-report question (typically “loss of consciousness”) to identify brain
injury and failure to classify the degree and extent of injury (8).
Of even greater concern is that there are only three prospective studies
examining the prevalence of brain injury among patients entering substance use
treatment programs. The first study to examine rates of TBI among patients with
SUD was conducted in 652 inmates who used drugs as part of a large-scale
NIDA-funded health services study (114). In this cohort, 446/652 (68%)
reported at least one head injury, and 201/653 (31%) reported two or more
injuries (114). Patients with TBI reported significantly higher levels of alcohol,
cannabis, and sedative use in the 12 months preceding incarceration, along with
other lifetime health-related problems including respiratory, musculoskeletal,
circulatory, gastrointestinal, neurological, and skin disorders (114). Those with
two or more injuries had significantly more lifetime health problems than those
with one or no injuries (114).
A second study examined TBI rates among 7784 adults entering SUD
treatment in a state-funded community substance abuse treatment center (58).
Out of 7784 patients, 31.7% reported one or more TBI with loss of
consciousness (58). Patients reporting two or more TBIs with loss of
consciousness were more likely to have depression, anxiety, suicidal thoughts
and attempts, violent behavior, trouble concentrating, and more substance use
compared to those with none or one TBI (58). In a third study, rates of TBI were
higher (30%) in 95 patients with a cocaine use disorder than in 75 healthy
control subjects (8%), and TBI often preceded initiation of cocaine use (115).
Taken together, these findings suggest that TBI screening should be
considered as part of a routine intake process to facilitate early detection of head
injury. As previously mentioned, screening instruments range in length and
comprehension, but they all ask a few key questions that would indicate an
injury to the head, a loss of consciousness, change in behavior, and difficulty in
concentration, thinking, or remembering. At the least, early detection could
identify patients with TBI treatment needs, allowing clinicians to consult with
specialty care providers and/or to provide education regarding symptoms of both
conditions and coping strategies to minimize symptom impact (116).
In practice, SUD clinical staff are typically not adequately trained in the
assessment of TBI and are not familiar with acceptable screening/assessment
tools and diagnostic criteria. One potential goal for assessing TBI is to identify
clinical characteristics that may require special treatment accommodations or
varying treatment approaches (58). Both SUD and TBI can present with
overlapping and complicated neurocognitive and behavioral problems, which are
difficult to discriminate. Both diagnoses also commonly present with other
comorbidities such as anxiety, depression, and PTSD, further complicating the
TBI diagnostic assessment. Therefore, properly trained clinicians are advised to
use the following standard measures of TBI assessment: The VA TBI
Identification Clinical Interview (27), WARCAT (28), Structured Interview for
TBI Diagnosis (29), Ohio State University TBI Identification Method (24,25), or
BAT-L (26). Additional neurocognitive testing and/or neuroimaging may be used
to establish the presence of and track change in the associated symptoms of a
TBI but can be used only to support a TBI diagnosis to the extent that these
symptoms cannot be accounted for by causes other than TBI itself. Of note,
routine clinical imaging is insensitive to most mTBIs. In sum, each clinician will
use TBI assessment tools differently depending upon their role and degree of
training. Clinical staff are advised to consult with specialty providers in the
management of uncovered TBI symptomology accordingly.
Uncovering of a self-reported head injury may provide an indicator that
other mental health and cognitive problems are present and may need proper
evaluation and management (114). Upon identification of TBI, SUD clinicians
can offer treatments that emphasize the prevention of risk-taking behaviors that
may lead to reinjury, the resumption of work, social and other interpersonal
obligations, and accommodation strategies for limitations related to poor
cognitive function.
FACTORS INFLUENCING RECOVERY

FROM TBI
Severity of brain injury, age, and preinjury functioning can influence outcomes
after TBI. Older adults who sustain a TBI have lower survival rates and less
favorable outcomes than those who sustain a TBI during young and middle
adulthood (117,118). Persons with higher levels of preinjury cognitive
functioning often preserve more functional capacity after TBI (119). Social–
environmental factors, such as social support, caregiver and family functioning,
and socioeconomic status can influence the effectiveness of rehabilitation
treatments (120). Poor psychological adjustment, social difficulties (121,122),
learning disabilities (123), history of previous neurological or psychiatric
disorders (121,124), and preinjury unhealthy use of alcohol or drugs (125) can
also complicate assessment and treatment of TBI.
Returning to participation in preinjury social roles is an important aspect of
functioning for adults following a TBI. The ability to function in social roles is
influenced by caregiver and family support, independent of TBI severity (126).
Social–environmental factors, such as the ability to live independently, maintain
employment, or be involved in meaningful interpersonal relationships, can also
influence outcomes for persons affected by TBI (127,128). Economic and social
disadvantage are associated with poor cognitive and academic outcomes
following severe TBI (129,130). Conversely, well-functioning caregivers and
available financial and social supports contribute to better recovery and
outcomes (131,132). As stated often in this chapter, SUD and TBI have great
overlap in symptoms that can affect recovery from both diagnoses.
TREATMENT APPROACHES FOR TBI

AND SUD
Although NIH and the American College of Surgeons call for the inclusion of
SUD treatment in brain injury patients, little work has been done to determine if
traditional SUD interventions are effective for patients with TBI (111,112,133).
In fact, some results have shown that traditional SUD treatment may be
relatively ineffective for patients with TBI due to cognitive, behavioral, physical,
and emotional deficits that occur after brain injury (133). More effective care
may be provided by accommodating or matching patients with treatment
approaches that address specific deficits. However, the literature pertaining to
treatment matching is nonexistent and much work needs to be done prior to
making evidence-based recommendations. In this section, we will provide an
overview of special cognitive, rehabilitative, and pharmacotherapy approaches
for TBI and SUD and cotreatment of both TBI and SUD where evidence is
available.
Cognitive Rehabilitation for TBI

In reviewing 370 published studies on cognitive rehabilitation in 1246
participants with TBI and stroke, Cicerone et al. (134) concluded that cognitive
rehabilitation is clearly the best available form of treatment for people who
exhibit neurocognitive impairment and functional limitations following TBI. He
further noted that there is substantial evidence to support interventions for
attention, memory, executive function, social communication skills, and
comprehensive–holistic rehabilitation after TBI. We present a brief overview of
cognitive rehabilitation techniques for TBI that overlap with three common
cognitive deficits also occurring in SUD: attention, memory, and executive
function.
Attention Training
Although attention training has its limitations (134,135), ACRM Cognitive
Rehabilitation Task Force recommends remediation of attention as a standard
practice during postacute rehabilitation from TBI (134,135). ACRM further
recommended that remediation of attention deficits should include both direct
attention training and cognitive training as an adjunct to clinician-guided
treatment to promote development of compensatory strategies and foster
generalization to real-world tasks (134).
An example of direct attention training is Attention Process Training (APS),
designed to improve attention skills through a set of standardized auditory and
visual procedures made challenging by systematically increasing level of
distractions (136). This intervention organizes attention and concentration tasks
into subcomponents of sustained attention, selective attention, alternating
attention, and divided attention. Training procedures place gradually increasing
demands upon attentional capacity by using visual and auditory distractors and
combining single tasks into dual-task procedures where the patient must
alternate attention or divide attention across simultaneously presented
procedures.
Memory Exercises
Memory training has a controversial past. Therapies based on repetitive drills
have shown little evidence of efficacy. However, other approaches to memory
training, including mnemonic techniques and other memory-enhancing strategies
fostering development of techniques to enhance registration and encoding of
information and development of memory search methods, have shown efficacy.
Memory strategy training appears to be most effective for persons with mTBI
and/or mild memory impairment, with decreasing effectiveness as injury severity
and memory impairment increase (134,137).
External aids have been used to address memory and executive function
impairments. The majority of more recent memory training studies have focused
upon the use of memory notebook and electronic equivalents, essentially serving
as “memory prosthetics.” Several studies have compared different memory
notebook formats and training procedures to identify the most effective. A recent
study combined strategy training with memory notebook training, and found
improvement in both the use of memory prosthetics as well as the use of
memory strategies, with improvements extending into patients’ everyday
memory functioning (138).
Executive Functions
Executive functions refer to those cognitive abilities required for formulating
goals, planning how to achieve them, and carrying out the plans effectively.
These functions are critically important in social and vocational situations and
are a specific target of cognitive remediation. There is increasing support for the
proposition that training-based therapies targeting problem solving may improve
functioning in individuals with traumatic brain injury. Programs that allow
individuals to practice planning, analyzing, and applying personally and
functionally relevant tasks and goals, monitor task performance, and evaluate
outcomes have been associated with improved functional skills.
Several interventions have been developed and successfully implemented
with such an approach. For example, Goal Management Training (GMT)
emphasizes the cessation of ongoing activity, and a cognitive strategy for
breaking down goals into manageable substeps; learning of these strategies
improves goal management on tasks (139). A second intervention combines
attention and problem solving (APS) as targets of therapy in a group-based
training protocol. Initial group sessions address attentional difficulties, and later
sessions introduce and practice the use of problem-solving strategies. During
group sessions, participants are encouraged to adopt a systematic approach to
solving problems and to manage and monitor goal achievement through periodic
mental checking. In 2009, a study of participants with chronic frontal lesions
showed improvement on a functional measure and on caregiver ratings of
executive functioning, after the implementation of the APS training relative to
control conditions (140).
Goal-oriented attentional self-regulation (GOALS) is another manualized
group intervention that targets attention regulation skills during the first phase of
training, and application of trained attention regulation and goal management
strategies to individually defined real-life goals during the second part of
training. GOALS participants with chronic brain injury show improvements in
cognitive domains such as attention and executive function, performance on
complex “real-life” functional tasks, and self-reported use of trained strategies in
daily lives, including ability to stop, relax, and refocus (SRR) during stressful
times (141).
Cognitive Rehabilitation Summary and New

Directions
The rehabilitation of cognitive deficits following brain injury has shown
significant growth over the last three decades, despite the complexity of the
problems being treated and the difficulty in designing valid scientific studies to
guide therapy. Nevertheless, cognitive rehabilitation training has been repeatedly
shown to improve processes such as attention, memory, and executive functions
after brain injury. Compensatory interventions, such as electronic or prosthetic
memory book devices and electronic alerting systems, also help improve
functional skills. Furthermore, cognitive rehabilitation therapy techniques have
been successfully applied to the problems of social integration and vocational
training. Experience suggests that the most effective therapy occurs when
cognitive training is conducted in real-life situations and has high interest to the
individual. Unfortunately, no cognitive rehabilitation strategies have been tested
simultaneously for SUD and TBI. However, there is value to begin examining
strategies which target impairments characteristic to both SUD and TBI patient
populations.
Pharmacological Interventions for SUD and

TBI
Very little is known about the pharmacological treatment of SUDs in individuals
with TBI and there is limited evidence to inform clinical care.
Possible medications for treating SUD in individuals with TBI can be
broadly lumped into two categories: (a) “SUD pharmacotherapies”—
medications that are known to be effective for SUD and that are used in patients
without TBI and (b) “TBI pharmacotherapies”—medications that have been
shown to have some utility for TBI treatment in patients without SUDs.
SUD pharmacotherapies—medications that are clearly proven to be
effective for SUD treatment and have been approved by the United States Food
and Drug Administration (FDA)—are currently available for only three classes
of substances: alcohol, opioids, and nicotine (tobacco). These are discussed in
detail elsewhere in this text. There are no FDA approved medications for the
treatment of stimulants, cannabis, hallucinogens, and other substances.
TBI pharmacotherapies—medications that have been utilized in the
treatment of patients with TBI—include those used to treat cognitive
impairments as well as some of the epiphenomena associated with TBI, such as
headache and seizures. The medications that have been applied to improve
cognition—primarily catecholaminergic therapies—have been beneficial for
memory and attention recovery (66) but lack reproducibility and have not been
translated into standard clinical practice (69).
Pharmacotherapy of Alcohol Use Disorder in Individuals

With TBI
The following discussion focuses on the available published data on the
treatment of individuals with TBI and SUDs with medications that are either
known SUD pharmacotherapies or TBI pharmacotherapies.
Although there are four FDA-approved medications for the treatment of
AUD, including disulfiram, acamprosate, and both oral and extended-release
injectable naltrexone, there are no published reports of the use of any of these
medications in patients with TBI.
A fifth medication, topiramate, although not FDA approved for AUD
treatment, is also known to be efficacious (142) in reducing alcohol use.
Topiramate is thus an off-label AUD pharmacotherapy. It is also a form of “TBI
pharmacotherapy” when it is used to treat TBI-related headache (143). To date,
topiramate is the only medication that has been tested in a prospective controlled
trial to treat AUD in patients with TBI (AUD/TBI). In a double-blind,
randomized controlled study of 32 veterans with AUD and mTBI, topiramate in
doses up to 300 mg/d showed a signal for alcohol use reduction although not for
TBI symptom reduction (144). However, topiramate treatment was associated
with cognitive impairment, with deficits in verbal learning and memory that
appeared to resolve with tapering off medication. In conclusion, while
topiramate may help reduce alcohol use, it may aggravate cognitive impairment
in individuals with mTBI.
Another anticonvulsant, valproic acid, has also been tested in two small
clinical studies focusing on alcohol use in individuals with TBI. The first of
these studies was a small open-label pilot trial that found pre-/post reductions in
alcohol use and in symptoms of mood lability (145). A second study with
valproic acid, utilizing a placebo-controlled methodology, has been completed,
but results are not yet published (146).
Pharmacotherapy of Nonalcohol SUDs in TBI

To date, there are no published reports of clinical trials employing
pharmacotherapy to treat SUDs other than AUD. Specifically, there are no
reports of pharmacological treatment of opioid stimulant, sedative–hypnotic,
cannabis, or other nonalcohol SUDs in patients with TBI.
SUD Pharmacotherapies Used to Treat Non-SUD Symptoms in

TBI
Regarding the use of SUD pharmacotherapies for non-SUD indications in
patients with TBI, there are two published reports of naltrexone treatment,
describing a total of three cases (147,148). These case reports describe the use of
naltrexone, an opioid antagonist, to improve TBI symptoms, not SUD. The
experimental use of naltrexone was based on animal studies that suggest that
opioid antagonists such as naloxone may be helpful in reducing the effects of
acute brain injury (147,149). Tennant (148) described placebo-controlled within-
case studies involving two patients whose postconcussion symptoms were
improved by naltrexone treatment. Another case report (147) described the open-
label use of oral naltrexone for a non-SUD indication in a patient after severe
brain injury, to enhance motor, speech, and overall functional recovery, not as a
treatment for SUD. The patient in this case was described as showing
accelerated improvement in functional status following naltrexone treatment.
There are no reports on the use of partial or full opioid agonist
pharmacotherapies such as buprenorphine or methadone treatment in patients
with TBI. Nor are reports available for smoking cessation pharmacotherapies in
patients with TBI.
Pharmacotherapy for SUD and TBI: Future

Directions
The use of catecholaminergic (particularly dopaminergic medications) remains a
research approach to pharmacotherapy of both TBI-related cognitive
impairments (69) as well as SUDs. These medications include stimulants and
other dopaminergic agents such as antiparkinsonian medications, some of which
have been shown to have modest efficacy in trials in stimulant use disorders.
Examples are D-amphetamine and bupropion–dopaminergic medications that
have been found to have modest efficacy in cocaine use disorder (150).
Stimulants and bupropion have also been judged to have modest efficacy in
methamphetamine use disorder (151).
Clinical research on the feasibility and effectiveness of both known and
experimental SUD pharmacotherapies is needed in order to guide practitioners in
the use of medications for these co-occurring disorders. No clear evidence exists
that would prevent the use of currently approved pharmacotherapies for nicotine,
opioid, or AUDs in patients with TBI, but neither is there evidence regarding
their effectiveness in this population.
CONCLUSIONS
The co-occurrence of SUD and TBI is common and carries great neurocognitive,
neurobiological, affective, and functional harms along with higher rates of
mortality than either diagnosis alone. Numerous studies document a high
incidence of preinjury drug and alcohol use in patients with TBI, with high rates
of intoxication upon hospital admission. Both SUD and TBI are highly comorbid
with other medical and mental health problems including chronic pain,
depression, PTSD, and anxiety. Although the prevalence and associated harms of
these co-occurring disorders are beginning to be examined, much work is needed
to identify factors that may enhance current treatment interventions.
Patients with preinjury histories of substance use are at higher risk for
relapse following TBI. More study is needed on the prevalence of SUD
following TBI and to determine if the development of SUD postinjury is an
attempt to assuage TBI-related symptoms. If this is true, treatments aimed at
recovery of dysfunction and on improving emotional and pain distress tolerance,
coping, and accommodation are likely treatment targets. Barriers to accessing
these routine clinical treatments for SUD and TBI need to be identified and
reduced.
It’s imperative that current SUD and TBI screening and treatment
interventions (eg, pharmacotherapy and cognitive rehabilitation) are tested for
accuracy and efficacy in patients with these dual diagnoses. If current tools are
ineffective, it will be necessary to adapt or develop new interventions for this
unique patient population. Until these tools are available, treatment providers
should, at a minimum, screen for TBI in patients seeking SUD treatment. Upon
discovery of TBI, clinicians should offer treatment emphasizing reduction of
risk-taking behavior and accommodate for any limitations that prevent full
benefit from known drug and alcohol treatments. Providers are also encouraged
to seek consultation from specialty services such as neurology and rehabilitation
medicine and modify current treatment approaches to accommodate the
neurocognitive deficits common in these dually diagnosed patients.
In sum, the problems associated with co-occurring TBI and SUD are
bidirectional and complex. Our understanding of the underlying neural
mechanisms and associated dual treatment options for these comorbidities is in
its infancy. Recent academic and media attention have resulted in a growing
literature examining these conditions with the aim of developing new innovative
treatment strategies, ultimately reducing the harm and burden associated with
these co-occurring conditions.
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CHAPTER 40
Military Sexual Trauma
Joan E. Zweben
CHAPTER OUTLINE
Barriers to Reporting Sexual Assault
Military Culture
Clinical Issues
Getting Help at the VA
Conclusions
With over a million active duty military returning to the United States, U.S.
community treatment providers will inevitably meet them when they decide to
seek help for their unhealthy substance use. Often, this does not happen quickly.
It can take a few months or years for veterans to decide that their alcohol,
nicotine, and/or other drug use is actually a problem, and they may be moved
along by clinicians treating them for depression, posttraumatic stress disorder
(PTSD), or other conditions causing them distress. Although the U.S. Veterans
Affairs (VA) Medical Centers can offer excellent comprehensive care in many
communities, those who have experienced sexual trauma in the military, in
particular, may refuse to seek help there because they have complex feelings
about such trauma. When these men and women appear in community settings,
or to private practitioners, it is essential that they are met by professionals with
some understanding of their issues. A significantly higher percentage of women
are assaulted, but men outnumber women in the military. Though the
percentages reporting assault are lower, the actual numbers are almost equal (1).
Outside of the VA, men may be less likely to be screened for sexual trauma than
women.
Despite the strong commitment of the U.S. Department of Defense (DOD) to
address sexual assault, both men and women continue to report devastating
experiences of sexual assault and subsequent betrayal by their command when
they seek accountability. Emerging data support the view that the problem is
complex. These include barriers to reporting, failure to hold perpetrators
accountable, and retaliation against victims. Currently, the DOD is making
comprehensive prevention and intervention efforts (2), but the legacy will
remain for some time.
According to the VA, “Military sexual trauma (MST) is sexual harassment
and/or sexual assault experienced by a military service member regardless of the
geographic location, the gender of the victim, or the relationship to the
perpetrator. Both men and women can experience MST, and the perpetrator can
be of the same or of the opposite gender. Perpetrators may or may not be service
members themselves (1).”
Since 2012, the DOD has devoted a great deal of attention to preventing and
appropriately addressing sexual harassment and assault and can demonstrate
steady improvement. The estimated number of service member victims was 26
000 in FY 2012, 20 300 in FY 2014, and 14 900 in FY 2016. The DOD began
implementing strategies to reduce barriers to reporting, and since 2012, there
was a significant increase in victim reports of sexual assault (1). Service
members have several pathways open to them. A restricted report allows victims
to confidentially access medical care and advocacy services without triggering
an investigation. An unrestricted report is provided to command and/or law
enforcement for investigation. Service members may reclassify their report as
unrestricted at any time and participate in the military justice process. Over time,
the rate of unrestricted reports has risen, and restricted reports have converted
more quickly.
According to a 2014 RAND study, there was a decline in the percentage of
active duty women who experienced unwanted sexual contact from an estimated
6.1% (26 000) in 2012 to an estimated 4.3% (18 900) in 2014. Approximately
72% of those who reported their assault said that they would make the same
decision if they had to do it again (3). DOD continues its efforts to prevent MST
through systematic efforts at prevention and checks and balances once reports
are made.
BARRIERS TO REPORTING SEXUAL

ASSAULT
Many of the barriers to reporting are common to other victims of sexual assault;
some are more characteristic of military members. Service members may
minimize the seriousness of the experience or be too embarrassed to report it.
They may fear not being believed, of being blamed, or of having their reputation
suffer. In the military, they may have a well-founded fear of harm or retribution
if they report it, as there unfortunately are numerous examples often shared by
military members among themselves and discussed in the media (4). They may
fear for their career. They may also be concerned that their own behavior, such
as alcohol and other drug use and fraternization offenses, may undermine their
efforts to hold perpetrators accountable. For all these reasons, they may seek
help in community settings once they leave active duty.
MILITARY CULTURE
Clinicians are beginning to acknowledge that the military has a distinctive
culture as complex as others routinely discussed under the theme of cultural
competence. It is important to make an effort to learn on your own and also let
your patient teach you about what was important to him or her. What branch did
the patient serve in, and what are the distinctive features of that branch? Did the
patient serve in peace time or war time? What was their job? There are great
differences between Vietnam-era U.S. veterans and those who served in
Afghanistan (OEF) and Iraq (OIF). Because of the nature of the wars in
Afghanistan and Iraq, it is safe to assume that all veterans who served there are
combat veterans, even if that is not in their official job description.
Cultural values in the military include a strong emphasis on honor, respect,
and obeying the chain of command. These can be positive forces in treatment.
Community programs working with homeless veterans have noted a heartening
level of follow-through once treatment plans have been agreed upon. The value
placed on “leave no one behind” can be a positive factor in recognizing the value
of cohesion in treatment groups and working to promote it. However, military
values can also be impediments to seek and utilize help. The value placed on
protecting yourself may add to the shame the patient feels about the sexual
assault and make it more difficult for them to report it. They may feel like they
“should have been able to fight my perpetrator off.” This is particularly true for
men, who are even more likely to feel they should have been able to overpower
the assailant and prevent the assault (5). Respect for authority turns to a
profound sense of betrayal when officers higher up actively discourage reports,
avoid investigating, and fail to impose serious consequences on perpetrators.
CLINICAL ISSUES
It is important to screen for MST when patients seek care for physical or
psychiatric conditions. This is now standard practice in the VA and should be in
community medical care as well. This requires creating a comfortable climate
for disclosure, unhurried, with adequate privacy. Interruptions should be
minimized as much as possible. In general, patients are willing to answer
specific questions if the clinician is perceived as nonjudgmental and potentially
helpful. Questions can be asked as part of the social history, explaining to the
patient that these experiences are sufficiently common in the military and that
the questions are routine. The two questions recommended by VA protocols (6)
are as follows:
Did you receive uninvited and unwanted sexual attention, such as touching
or cornering, pressure for sexual favors, or verbal remarks?
Did someone ever use force or the threat of force to have sexual contact
with you against your will?
It is important to manage and limit the initial disclosure process, to assess

current status and safety, and to be prepared to offer mental health services or
make an appropriate referral.
One of the most prominent issues these patients will present with is
substance use and PTSD. There are high rates of childhood trauma among
veterans in general, particularly those who experience MST (7). Multiple
traumatic experiences in childhood and adulthood exacerbate the PTSD and
often increase the severity of the substance use. In the military, as in other
situations, a victim may be continually seeing and working with the perpetrator
during workplace or other military settings, adding to the difficulty. Often, the
risk is ongoing.
Treatment with these patients is often tempestuous. They are often highly
anxious and irritable and may be prone to angry outbursts. It can be difficult to
establish a therapeutic alliance, particularly if the therapist is of the same gender
as the perpetrator. Working with a treatment team is helpful, as multiple
treatment contacts with different individuals may be necessary for engagement,
and these patients may need a higher level of care than a solo practitioner in the
community can provide. These patients can be highly crisis prone, and a
treatment team can help sort out their many complexities and arrive at a viable
plan. A treatment team can also help the clinician avoid becoming too self-
critical and discouraged, while utilizing a forum for self-examination.
Given the potential for severe PTSD symptoms and the high suicide rates of
military members, clinicians must address the issue of guns. It is appropriate to
assume that the patient, whether male or female, has at least one weapon in their
home and that this weapon is an important part of their identity. Ask specific
questions about how he or she stores the weapon and the bullets. If lethality is an
issue, attempt to negotiate storing ammunition with a friend or getting a trigger
lock. All VA patients are eligible to receive gun locks at no charge, and they may
be available to other veterans upon request. Weapons may be turned into the VA
police. It is advisable to put comparable arrangements in place for patients to
surrender their weapon if they express willingness to do so.
Women with MST present with a variety of medical problems. They may
report chronic pain, such as headaches and back or pelvic pain. They can have a
variety of gynecological problems: sexual dysfunctions, menstrual
abnormalities, menopausal symptoms, or reproductive symptoms.
Gastrointestinal symptoms include diarrhea, indigestion, nausea, and difficulty
swallowing. Other complaints can include chronic fatigue, sudden weight
changes, and heart palpitations. These may be the vehicle through which the
woman asks for help, as a nurse or primary care physician may be less
threatening. It is important to rule out organic causes prior to ascribing the
symptoms to MST.
Men who reported either sexual harassment or assault were more likely to
have a history of sexual trauma and alcohol-related problems as well as poorer
baseline physical and mental health. Men with MST are more likely to have
sexually transmitted diseases, such as HIV/AIDS, syphilis, and herpes, as well as
disorders of sexual desire and arousal (5). They were more likely to report
symptoms of PTSD and depression (8). They report stronger symptoms at the
beginning of treatment and perceive their general health as more damaged (5).
Conducting a physical examination or doing medical procedures can also
present challenges. It is important to make the medical encounter as safe as
possible by providing a private, calm setting and explaining what to expect. If
the patient becomes upset, or begins to dissociate, it is important to stop
touching the patient or discontinue the procedure and then reorient and soothe
the patient. A well-established pathway for mental health referrals and a “warm
handoff” is part of good care, as these patients may be reluctant to seek this kind
of help and give up easily if the referral is not guided at each point that obstacles
might occur.
GETTING HELP AT THE VA

Although many women in particular will emphatically refuse to go to the VA, it
is important for them to know what it has to offer, particularly if other resources
in the community are scarce. A pioneer in the use of electronic records in the
1980s, the VA has used them to identify the factors involved in good outcomes
and then formulate and disseminate protocols to improve care across the system.
The result is that VA care produces better outcomes for chronic conditions such
as diabetes and hypertension than Medicaid and the private sector (9,10). All
veterans seen in VA health care are asked if they experienced MST. All treatment
for physical or mental health conditions related to MST is free. Every VA
healthcare facility has a designated MST coordinator who serves as the contact
person for MST-related issues. Many veterans are confused about their eligibility
for benefits and should be encouraged to get into the system (Table 40-1), in case
they lose their current insurance or later need care they cannot access in the
community.
TABLE 40-1 Resources
CONCLUSIONS
Community treatment providers can expect to see veterans who are MST victims
in their programs and should prepare to address their complex needs. Many will
have highly conflicted feelings about their military experience and may not even
share they are a veteran unless specifically asked “have you been in the
military?” Although the VA has worked hard to provide excellent services to
these patients, many will not consider seeking help in that setting. Community
providers who are knowledgeable about the culture of the military will be better
able to engage them. Their traumatic experiences will influence their efforts to
address their physical and emotional problems, as it affects everything from their
ability to tolerate a physical exam to their emotional stability and participation in
a recovery process. Expertise in addressing PTSD is a must for substance use
disorder treatment to be effective for this group. Their training often enhances
the character assets they bring to the recovery process, and they can be very
rewarding to work with.
ACKNOWLEDGMENTS
The author thank John Straznickas, MD, Associate Clinical Professor, University
of California, San Francisco and Team Leader, Substance Use Posttraumatic
Stress Disorder Team, San Francisco Veteran’s Affairs Medical Center.
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CHAPTER 41
Alcohol, Prescription, and Other Drug
Problems in Older Adults
Frederic C. Blow and Kristen L. Barry
CHAPTER OUTLINE
Introduction
Alcohol Use Guidelines for Older Adults
Scope of the Problem in Older Adulthood
Alcohol and Prescription Medications
Nonmedical Use of Prescription Medications
Issues Unique to Older Adults
Screening and Detection of Alcohol and Nonmedical Use of prescription
Medications in Older Adults
Intervention Strategies for Older Adults
Limitations of Treatment Outcome Research
Conclusion
INTRODUCTION
The increase in illnesses in later life leads to higher utilization of health care
among older adults (1–5), and many of the medical and psychiatric disorders
experienced in aging are influenced by lifestyle choices such as drinking alcohol
and nonmedical use of prescription medications. Older adults are more
vulnerable to the effects of alcohol and medications and, combined with their
increased risk for comorbid diseases, may seek health care for a variety of
conditions that are not immediately associated with alcohol or nonmedical use of
prescription medications. These risks include harmful drug interactions, injury,
depression, memory problems, liver disease, cardiovascular disease, cognitive
changes, and sleep problems (6–11). Older adults with at-risk or harmful alcohol
use are a special and vulnerable population who may require older adult-specific
screening and intervention procedures (see definitions below). At-risk and
harmful use is the largest class of substance use problems seen in older adults.
Unhealthy use of substances, including alcohol, is more common in the older
cohort born after World War II (persons born between 1946 and 1964) (12,13)
compared to earlier cohorts. This may be due partly to changes in attitudes and
behaviors toward the use of alcohol and drugs with the “baby boom” generation
(14). Research indicates that the baby boom cohort may need more intervention
and treatment options than have been available for prior generations (15–19).
ALCOHOL USE GUIDELINES FOR
OLDER ADULTS
To understand who might benefit from interventions and/or treatments, it is
important to address the terms used for different classifications of use. The
NIAAA and the Center for Substance Abuse Treatment (CSAT) Treatment
Improvement Protocol (TIP) on older adults recommended that persons, male or
female, age 65 and older consume no more than one standard drink per day or
seven standard drinks per week (20,21). In addition, older males should consume
no more than four standard drinks on any drinking day and older women no
more than two to three drinks per day. These drinking limit recommendations
come from data regarding the relationship between level of consumption and
alcohol-related problems (22–24). Drinking guidelines also highlight an
important distinction between problem drinking or at-risk drinking and DSM-
IV–defined alcohol dependence. Clarification of terms is essential in a
discussion of alcohol use.
At-risk Use: Use that increases the chances that an individual will develop
problems and complications. Persons older than age 65 who drink more
than seven drinks per week—one per day—are in this category.
Harmful Use: Older adults engaging in harmful are drinking at a level that
has already resulted in adverse medical, psychological, or social
consequences. Potential consequences can include injuries, medication
interaction problems, and family problems. Because of aging-related
physiological changes, some older adults who drink even small amounts of
alcohol can experience alcohol-related problems. In addition, older adults
engaging in a pattern of psychoactive substance use that is causing damage
to health have harmful use of those substances. The damage may be
physical (eg, hepatitis following injection of drugs) or mental (eg,
depressive episodes secondary to heavy alcohol intake). Harmful use
commonly, but not invariably, has adverse social consequences; social
consequences in themselves, however, are not sufficient to justify a
diagnosis of harmful use.
Use Disorder: In the DSM-5, the diagnostic criteria for a use disorder
include but are not limited to a compendium of psychosocial problems.
Anyone meeting 2 of the 11 criteria during the same 12-month period may
receive a diagnosis of AUD. A minimum of 2-3 criteria is required for a
mild substance use disorder (SUD) diagnosis, while 4-5 is moderate, and 6-
7 is severe.
SCOPE OF THE PROBLEM IN OLDER

ADULTHOOD
Alcohol
Significant advances have been made in the last two decades in the
understanding of the aging process, and new attention is being paid to the
intersection of the fields of gerontology/geriatrics and alcohol studies.
Prevalence estimates and typical characteristics of older problem drinkers have
been reported over the last 20+ years (18,25–28). Specific treatment and
intervention strategies for older adults with at-risk or harmful drinking are
beginning to be disseminated. It can be important for diagnosis and treatment
planning to distinguish older adults who have a history of at-risk or harmful
alcohol use (early onset) compared to those that do not develop problems related
to alcohol until later in life (late onset). Individuals with early onset had at-risk
or harmful drinking patterns prior to the age of 40, while late-onset drinkers
typically began drinking until later in life, possibly due to stressors that develop
with aging (eg, retirement, loss of income, loss of partner, etc.). Treatment for
early-onset drinkers may be complicated by long-term denial, medical
comorbidities, limited social support, poor emotional skills, and cognitive
impairment. It is estimated that approximately two-thirds of older adults with
alcohol use disorders (AUDs) belong to this category (29). Late-onset drinkers
had problems with alcohol at various periods earlier in life, but have had stable
periods of abstinence or low-level drinking over a long period of time. It is
important to note that late-onset drinkers may appear “too healthy” to raise
providers’ concerns. As a result, it is important for clinicians to ask their older
patients about lifetime substance use patterns, because problems can arise with
stressors in older adulthood (26,30).
At-risk drinking increases the potential for developing problems and
complications. The prevalence of at-risk drinking among older adults ranges
from 1% to 16% (31–33). These rates vary widely depending on the definitions
of older adults, alcohol measurements, cutoff point to determine at-risk or
harmful use, and the sampling methodology. The 2015 National Survey on Drug
Use and Health (NSDUH) (34) found that in the past month, for individuals over
50 years of age, 5.4% were heavy drinkers and 19.7% were heavy episodic
(binge) drinkers (more than four drinks on a drinking occasion). The 2015
NSDUH also showed that 4% of individuals over fifty reported an alcohol use
disorder (AUD) in the past year.
In 2015, 4.6% of those aged 55-59, 3.6% of those aged 60-64, and 1.4% of
those aged 65 or older met criteria for DSM-IV–defined alcohol dependence
(34). Most older patients experiencing issues related to their drinking are
unidentified by their healthcare personnel. Signs and symptoms of issues that
could be related to alcohol and other substance use in older adults are shown in
Table 41-1. Few older adult patients with harmful drinking or dependence seek
help in specialized addiction treatment settings on their own. Given the high
utilization of general medical services by older adults, primary care physicians
and other healthcare professionals are essential for identifying those in need of
treatment (19,35).
TABLE 41-1 Signs and Symptoms of Potential Alcohol

and Substance Use Problems in Older Adults: Time to
Ask Questions
Adapted from Barry KL, Oslin D, Blow FC. Alcohol Problems in Older Adults: Prevention and
Management. New York, NY: Springer Publishing, 2001.
Studies in primary care settings have found that 10%-15% of older patients met
criteria for at-risk drinking (7,36). In a large primary care study of 43 606
patients over age 65, Kirchner and colleagues (8) found that 4.6% of the men
and 1.5% of the women regularly drank in excess of National Institute of
Alcohol Abuse and Alcoholism (NIAAA) guidelines. Among moderate drinkers
(1-7 drinks per week), 10.2% had heavy episodic drinking 1-3 times in the past
month. Kirchner and colleagues also found that 21.5% were moderate drinkers
(1-7 drinks per week), 4.1% were at-risk drinkers (8-14 drinks per week), and
4.5% were heavy or binge drinkers (>14 drinks per week). Harmful drinking (in
Kirchner et al. defined as “heavy” drinking) showed significant positive
associations with depressive and anxiety symptoms and less social support.
Because patients with a previous history of at-risk and harmful use of
alcohol or other drugs are at risk for an exacerbation of these problems with
additional stressors, establishing a history of use can provide important clues for
future substance use concerns and can provide the opportunity to provide
prevention messages and encouragement to individuals who are maintaining
abstinence or very low use. Although it is generally assumed that life events
such as bereavement and serious illnesses can put the most stress on individuals,
any changes in life events (eg, retirement, change in income, etc.) can affect
alcohol use patterns.
Preliminary nursing home studies reported that 29%-49% of residents had a
lifetime diagnosis of an AUD, with 10%-18% reporting active AUD symptoms
in the past year (37,38). Klein and Jess (39) surveyed 111 intermediate care
facilities and homes for older adults and found that nearly three-quarters (72.4%)
of the healthcare workers surveyed believed that 10% or fewer of the residents
had a health problem related to earlier excessive drinking. In contrast to the
relative absence of alcohol-related health conditions reported by this sample,
most facilities (83.8%) did report at least some other problems, including
interactions with medications and other physical health concerns, that potentially
arose from the use of alcohol. Some assisted living facilities and nursing homes
offer a “happy hour” in order to encourage socialization among residents. Such
programs aimed at increasing sociability among residents may unwittingly can
give rise to alcohol problems in some residents. Residents could feel pressured
to drink in order to feel like they belong to the group, especially when
nonalcoholic beverages are not offered. There has been little research on alcohol
policies in residential living facilities. Empirical studies have found that some
facilities require nursing staff to retain and manage residents’ personal supplies
of alcohol (similar to medication dispensing), while staff at other facilities
provide very little oversight of residents’ alcohol possession and consumption
(39). More studies that examine alcohol-related policies and patterns within
nursing homes are needed. Training staff on best practices for the identification
and referral to treatment of alcohol-related issues among nursing home residents
is essential in this fast-growing aging adult population.
ALCOHOL AND PRESCRIPTION

MEDICATIONS
It is estimated that older adults account for more than one-third of all
prescription medications used in the United States (40). Older adults who drink
alcohol have an increased likelihood of being prescribed alcohol-interactive (AI)
medications (41). One study using the National Health and Nutrition
Examination Survey (NHANES) data showed a striking 77.8% of older adult
drinkers used AI medications (42). AI medications include central nervous
system agents, diuretics, cardiovascular agents, narcotics, and therapeutic agents
(42). Individuals can experience adverse reactions including falls, heart
problems, and liver damage. Taking AI medications on a regular basis and taking
multiple AI medications further increase the risk of adverse reactions, especially
among frequent drinkers. One study found that only 9.3% of adults age 65 and
older had ever discussed alcohol use with a health professional (43). These data
emphasize the need for physicians to discuss the potential risks of combining
alcohol with AI prescription medications with their patients, especially if the
patient has a past or current history of alcohol use.
NONMEDICAL USE OF PRESCRIPTION

MEDICATIONS
Opioids and Benzodiazepines
Although national data show that lifetime rates of nonmedical prescription drug
use disorders among older adults are low, compared to younger age groups, older
adults have still been found to have nonmedical use of sedatives, tranquilizers,
opioids, or amphetamines. The problematic use of prescription drugs by older
adults is not typically done to “get high” (44). Although there are individuals
who use prescription drugs to get high, many become problematic users
unintentionally due to pain, increased anxiety, and inability to sleep. Most
medications with nonmedical use are obtained by a prescription (11). The
medications of most concern for older adults are prescription medications that
affect brain function, resulting in changes in perception, pain, mood,
consciousness, cognition, and behavior. Of greatest concern are the opioid
analgesics and benzodiazepines used to treat anxiety and insomnia. These two
classes of medications are important foci because they are frequently prescribed
to older adults, have a high addiction potential, and interact with alcohol, all
increasing the risk of negative outcomes.
The existing literature on this topic, while scant, indicates that nonmedical
use of prescription medications affects a significant minority of the older adult
population (11,17,45,46). Attempts to quantify the prevalence of nonmedical use
of prescription medications among older adults have been limited in their scope
and generalizability of results (10). A survey of social services agencies
indicated that nonmedical use of prescription medications affects 18%-41% of
the older clients served, depending on the agency (47) and on how nonmedical
use is defined. They estimated that the nonmedical use of prescription
medications will increase for this age group to 2.7 million by 2020. Being
female, social isolation, a history of substance use or mental health disorders,
and medical exposure to prescription drugs with problematic potential were
associated with prescription medication problems.
Illegal Drugs
Most research conducted on substance use in older adults has focused on
alcohol. Rates of illegal drug disorders in older adults are poorly documented,
but thought to be very low (23). However, Lofwall and colleagues (48) noted
increased illicit drug substance use admissions among older adults (age 55 years
or older) from 1992 to 2005.
With the increased legalization and availability of cannabis as medicine, and
recreational marijuana, many older adults are using it to treat pain and promote
relaxation. Data from the 2002 to 2014 National Survey on Drug Use and Health
(NSDUH) indicate that marijuana use by older adults is on the rise. The
proportion of marijuana use in adults aged 65 or older increased more than
tenfold from 0.2% to 2.1%, and the proportion of adults aged 50-64 who
reported cannabis use in the past year more than tripled from 2.9% to 9.0% (49).
As the baby boom population ages, it is estimated that rates of marijuana among
older adults will continue to increase. Although it is not well known if marijuana
interacts with specific prescription drugs, it can intensify the effects of alcohol.
Studies have shown that cannabis affects both the central nervous system and
peripheral processes, anxiety, depression, cognition, learning, and motor
coordination. Its use is associated with increased injury and short-term memory
deficits.
Nicotine
Nicotine/tobacco use disorder remains prevalent across age groups. Most daily
smokers have nicotine/tobacco use disorder. In an analysis of the 2014 National
Health Interview Survey, the Centers for Disease Control and Prevention (CDC)
estimated that ~16.8% of adults ages ≥18 smoke, whereas 8.5% of those aged
65+ are current smokers (50). Older adults who smoke face health consequences
such as increased risks of lung cancer and chronic obstructive pulmonary disease
(51). Recent meta-analyses have also suggested a relationship between smoking
and decreased cognitive functioning. Further research is needed to clarify
causation (52,53). Research shows that persistent older adult smokers have
significantly higher levels of psychological distress when compared to quitters,
which should be kept in mind when implementing a cessation intervention.
Although nicotine replacement therapies and other technologies such as
bupropion or varenicline have advanced rapidly, there remains little information
specific to older adults on ideal dosing, adherence, and adverse events. However,
interventions aimed to reduce the prevalence of smoking among people can have
tremendous benefits.
Substance Use Disorder (SUD) Diagnostic

Classifications and Older Adults
Clinicians now generally rely on the criteria published in the American
Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition-Revised (DSM-5), for classifying alcohol-related problems. With
the release of the DSM-5, disorders previously understood as “substance abuse”
and “substance dependence” were found statistically and clinically to represent
one single disorder: a SUD. However, problems in classifying older adults
remain a concern (54–58). For example, the criteria for SUD may not apply to
older adults with substance use problems because older adults may not
experience a use of substances that results in a failure to fulfill major role
obligations at work, school, or at home. Individuals who are retired may have
fewer familial and work obligations (59).
ISSUES UNIQUE TO OLDER ADULTS

Older individuals may have unique patterns of drinking and nonmedical use of
prescription medications, substance-related consequences, social issues, and
treatment needs (60,61). See Table 41-1 for signs and symptoms of substance
use problems in this age group. Most older adults who are experiencing
problems related to their alcohol consumption may not technically meet criteria
for an AUD (59). However, drinking even small amounts of alcohol can increase
risks for problems. Older adults have increased sensitivity to substances as they
age, resulting in lowered rather than increased tolerance, particularly when
combined with the use of some over-the-counter (OTC) or prescription
medications (7,62,63). In addition, patients with co-occurring aberrant
medication-taking behaviors and chronic pain often find it hard to accept that
they have/are developing a SUD. Rather than finding treatment for opioid use
disorder (OUD), they seek alternative ways to obtain opioids, furthering
progression to OUD/opioid addiction. Although rates of opioid use and
nonmedical use of prescription opioids are lower in older adults when compared
to younger adults, mortality rates among older adults are increasing at a faster
rate than younger adults (64).
The use of nonjudgmental, motivational approaches can be a key to
successfully engaging these patients in care. Older adults present challenges in
applying brief intervention strategies for reducing use. Because of stigma, older
adults who drink at-risk levels often find it particularly difficult to acknowledge
their own risky drinking. In addition, chronic medical conditions may make it
more difficult for clinicians to recognize the role of alcohol, in particular, in
decreased functioning and quality of life. These issues present recognition
barriers for both clinicians and older adults in identifying the need for change. In
working with resistant patients who do not recognize a problematic level of
alcohol or drug use, clinicians can begin by teaching about changes in
metabolism with aging, the interactions between alcohol and specific
medications (especially sedatives), the potential for falls, and the relationship
between alcohol and some medical problems (eg, hypertension).
Co-occurring Disorders in Older Adulthood

Psychiatric comorbidities complicate interventions, treatments, and relapse
prevention. It is important to note that alcohol and other drugs can affect
emotional health long before psychiatric diagnoses are made, and early
interventions can be the key to maintaining emotional and physical health
functioning. Studies of older adults with SUDs find high rates of co-occurring
psychiatric illnesses, ranging from 21% to 66% (65–70). Illnesses, bereavement,
job loss, and retirement can all worsen depressive responses and increase alcohol
use. Chronic pain, difficulty sleeping, and anxiety are other factors that can
increase nonmedical use of prescription medications.
Sleep Medications
Although physiological changes in sleep–wake patterns can occur as part of the
normal aging process, sleep problems that lead to impairments in daytime
functioning, mood, and fatigue are not (71). While psychological interventions
such as cognitive behavioral therapy have been shown to improve perceived
sleep in older adults, sedative–hypnotic medications are the most commonly
prescribed treatment approach for insomnia among older adults. Medications
that treat insomnia include melatonin, herbs, nonbenzodiazepines, and sedating
antidepressants. Although benzodiazepines are most commonly prescribed for
sleep issues, studies show that benzodiazepine users report poorer-quality sleep
than nonusers (72). According to the 2012 American Geriatric Society Beers
criteria, benzodiazepines should not be used to treat insomnia in older adults due
to the increased risk of cognitive and psychomotor impairments, falls, fractures,
and motor vehicle accidents (73). However, users of the newer
nonbenzodiazepine hypnotics carry risks similar to benzodiazepines such as fall,
fractures, and delirium.
Comorbid Depression
Depression is not a normal part of aging. Mental health issues such as depression
have been recognized as major public health concerns in older adults and can
lead to serious consequences. The prevalence of older adults with comorbid
SUDs and mental disorders varies by population and shows wide ranges from
7% to 38% of those with psychiatric illness and from 21% to 66% of those with
SUDs (74). Research has shown a strong association between depression and
AUDs across age cohorts; that continues into later life. Depression and alcohol
use are the most commonly cited co-occurring disorders in older adults (13).
Studies of clinical populations have demonstrated the prevalence of
comorbid affective disorders and AUDs among older adults. A report
specifically examining the relationship of geriatric depression to co-occurring
SUDs found that approximately one-fifth of older adults with depression have a
co-occurring AUD (65). Similar rates of co-occurring disorders have been
reported in other studies of older adults in psychiatric outpatient clinics (15%)
and psychiatric inpatient settings (21%) (75,76). Data from the National
Epidemiologic Survey on Alcohol and Related Conditions (NESARC) found
that among high-risk alcohol users aged 60 and older, 24.9% met criteria for
major depression, 8.8% for anxiety disorder, and 5.9% for antisocial personality
disorder (77).
Further, a current SUD has been associated with the development of a new-
onset psychiatric disorder. For example, in a study of adults aged 60 and older
with an AUD, 4% developed a new major depressive disorder and 2% developed
a new generalized anxiety disorder over the span of 3 years, compared to 6.7%
of those with a drug use disorder who developed a major depressive disorder
(78). Rosen and colleagues (79) found 32.9% of DSM-IV–defined opioid-
dependent patients reported major depression in the past year. Blazer and Wu
(20) found major depression was associated with marijuana and cocaine use
among older adults.
At-risk and harmful drinking among older individuals is likely to exacerbate
existing depressive disorders. Patients with this comorbidity can be more
difficult to diagnose and treat because each illness may complicate the other
(80). Late-life adjustment disorders with depressed mood may be aggravated by
drinking to the point of meeting criteria for a depressive disorder (21). Co-
occurring addiction and psychiatric disorders among older adults are associated
with poor health outcomes, higher healthcare utilization, increased complexity,
poorer prognosis of mental illness, heightened mortality, higher rates of active
suicidal ideation, and social dysfunction compared to individuals with either
disorder alone (7,81,82). Although pharmacotherapies are common for
depression in older adults with co-occurring disorders, long-term data on the
effectiveness and safety of psychotropic drugs in older populations are scarce.
Selective serotonin reuptake inhibitors (SSRIs) are considered first-line therapy,
but older adults may be at an increased risk of side effects, such as falls,
cognitive issues, and hospitalizations (83). Psychotherapy and, to some extent,
lifestyle changes such as moderate-intensity exercise, improving nutrition, and
engagement in pleasurable activities and social interactions are all effective
psychosocial treatments for depression in older adults (84).
Comorbidity and Suicidality

Among all ages, the co-occurrence of diagnosed AUDs and mood disorders is
associated with greater suicide risk than either diagnosis alone. Oquendo and
colleagues (85) identified 1643 individuals with a lifetime diagnosis of bipolar
disorder from the 2001 to 2002 NESARC survey and found that more than half
(54%) of respondents who met the criteria for bipolar disorder also reported
AUD. Such individuals with comorbid AUD were at greater risk for a suicide
attempt than those without AUD. Examining mixed-age individuals with
depression and alcohol dependence, distinguished from patients with either
major depression or DSM-IV–defined alcohol dependence alone, Cornelius and
colleagues (86) found those with depression and AUD “suffer an additive or
synergistic effect of two separate disorders, resulting in a disproportionately high
level of acute suicidality upon initial psychiatric evaluation.”
Research has indicated that at-risk and even drinking within NIAAA
guidelines can aggravate affective disorders, such as depression, among some
older adults (87). Studies of treatment populations have demonstrated the
prevalence of comorbid affective disorders and AUDs among older adults.
Blixen et al. (88) found that 38% of older adults admitted to a psychiatric
hospital had both a SUD and another psychiatric disorder, most often depressive
symptoms or major depressive disorder. This all points out the importance of
conducting systematic screening for alcohol issues and comorbid psychiatric
conditions.
Weighing the Positive and Negative Aspects of

Alcohol Use
The evidence remains conflicted regarding the positive and negative aspects of
alcohol consumption. There is growing evidence that, among otherwise healthy
adults, especially middle-aged adults, moderate alcohol use may reduce
cardiovascular disease, may reduce the risk of some dementing illnesses, and
may have benefits in reducing cancer risk (89–92). Little research in these areas,
however, is conducted with older adults. Alcohol in moderate amounts may
improve self-esteem or provide relaxation. Levels of alcohol use that are often
considered moderate but are above recommended guidelines of no more than
one drink per day can pose challenges for clinicians who advise older adults
(38).
With the mixed opinions regarding the detrimental effects and potential
benefits of alcohol use, clinicians may feel confused regarding whether they
should recommend no change in consumption or a reduction in consumption for
older adults who do not meet criteria for a SUD. This ambivalence can lead to
clinicians recognizing at-risk drinking levels but not providing any
recommendations regarding use. Conigliaro and colleagues surveyed patients in
all age groups identified as “problem drinkers” who recently had a primary care
visit (93). The majority of the patients remembered having a discussion with
their doctor about drinking, but only half remembered being advised to reduce
consumption. For older adults who are more susceptible to both the
physiological and the psychosocial effects of substance use, erring on the side of
caution with nonconfrontational messages about the guidelines and following up
if there are concerns is generally the most practical and effective approach.
SCREENING AND DETECTION OF
ALCOHOL AND NONMEDICAL USE OF
PRESCRIPTION MEDICATIONS IN
OLDER ADULTS
The overall model and approach to the process of screening and intervening with
individuals who may have at-risk or problem use of alcohol and the nonmedical
use of prescription medications are called SBIRT—Screening, Brief
Interventions, and Referral to Treatment. Clinicians should screen for alcohol
use (frequency and quantity), drinking consequences, use of prescription
medications, levels of use, and alcohol/medication interactions. Screening can be
done as part of routine mental and physical health care and updated annually,
before the older adult begins taking any new medications, or in response to
problems that may be alcohol- or medication-related. The SAMHSA CSAT TIP
#26 expert panel on Substance Abuse Among Older Adults (7) recommended
screening all adults aged 60 plus on a yearly basis and when there are changes
that warrant additional screening (eg, major life events—retirement, loss of
partner/spouse, changes in health, etc.). Clinicians can obtain more accurate
histories by asking questions about the recent past. embedding the alcohol use
questions in the context of other health behaviors (ie, exercise, weight, smoking,
alcohol use), and asking straightforward questions in a nonjudgmental manner.
Additionally, a “brown bag approach,” where the clinician asks the patient to
bring in all medications, OTC preparations, and herbs in a bag to the next
clinical visit, is one potential means of getting reliable information about all
medication use. Many states allow physicians or pharmacists to query a state
database of controlled substance prescriptions without a patient’s consent. This
can reveal multiple prescribers for controlled substances, such as opioid
analgesics or sedative–hypnotics. Today, one must also ask about any cannabis
as medicine recommendations, prescriptions, or use. Used together, these
strategies allow the provider to determine what the patient is taking and what, if
any, interaction effect these medications, OTCs, and herbs may have with each
other and with alcohol. OTC preparation use often remains unevaluated in
clinical settings, and the use of some OTC preparations (particularly
anticholinergic agents) can be problematic in combinations with alcohol or
prescriptions.
Screening questions can be asked by verbal interview, paper-and-pencil
questionnaire, or computerized questionnaire. All three methods are reliable and
valid (94). Any positive responses can lead to further questions. To successfully
incorporate alcohol, prescription medication, and other drug screening into
clinical practice with older adults, one needs simple and consistent routines used
along with other screening procedures already in place (95).
Before asking any screening questions, the following conditions are helpful:
the interviewer needs to be empathetic and nonthreatening; the purpose of the
questions should be clearly related to health status; the information must be
confidential; and the questions need to be easy to understand. In some settings
(such as waiting rooms), screening instruments are administered as self-report
questionnaires with instructions for patients to discuss the meaning of the results
with their healthcare providers. However, screening instruments need larger
typefaces to accommodate patients with visual problems.
The following interview guidelines can be used. For patients requiring
emergency treatment or for those who are temporarily impaired, it is best to wait
until their condition has stabilized. However, assessing the current condition of
the patient can be done at any point, and signs of alcohol or drug intoxication
should be noted. Patients who have alcohol on their breath or appear intoxicated
may give incomplete responses, so consideration should be given to following
up the initial interview when the level of intoxication is not a factor. If the
alcohol questions are embedded in a longer health interview, a transitional
statement is needed to move into the alcohol-related questions. The best way to
introduce alcohol questions is to give the patient a general idea of the content of
the questions, their purpose, and the need for accurate answers (94). This
statement should be followed by a description of the types of alcoholic
beverages typically consumed. If necessary, clinicians may include a description
of beverages that may not be considered (eg, cider, low-alcohol beer).
Determinations of consumption are based on “standard drinks.” A standard drink
is a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz (a shot) of liquor (eg,
vodka, gin, whiskey).
Screening Process
The first step is to simply ask a few questions to rule out the majority of
individuals who do not need more systematic screening to determine the extent
of the problem (96). Screening generally identifies at-risk and harmful use, while
more extensive assessment can measure the severity of the substance use
symptoms and consequences associated with use, factors that may be
contributing to a SUD, and other characteristics of the problem. The screening
process should help determine if a patient’s substance use is appropriate for brief
advice/interventions or if it warrants a more intense approach. For example, the
following alcohol questions, adapted from the Alcohol Use Disorders
Identification Test (AUDIT) (Table 41-3), make an easy-to-use screening
instrument (97). The screening questions for prescription medications simply
ascertain if the older adult is using any of the targeted medications.
Initial Screening Questions: Alcohol

Initial question: Do you drink beer, wine, or other alcoholic beverages?
Follow-up questions: If yes, how many times in the [past year; past 3 months;
past 6 months] have you had four or more drinks in a day (for men)/three or
more drinks in a day (for women)? (Binge drinking question)
On average, how many days per week do you drink alcoholic beverages? If
weekly or more: On a day when you drink alcohol, how many drinks do you
have? (Quantity × frequency = consumption)
[An older adult who either reports binge drinking or drinking above NIAAA
guidelines can complete follow-up screening questionnaires (see below,
Screening Questionnaires).]
Initial question: Prescription Medications
Initial questions: Do you use prescription medicines for pain? anxiety? sleep?
Do you use any of these prescription drugs in a way that is different from how
they were prescribed?
Follow-up: If yes, follow up with additional questions regarding which
substances, frequency, and quantity of use.
Screening Instruments
Screening for alcohol use is not always standardized; and not all standardized
instruments show good reliability and validity with older adults. In addition to
quantity/frequency questions, the Michigan Alcoholism Screening Test-Geriatric
version (MAST-G); the shortened version, the Sort Michigan Alcoholism
Screening Test-Geriatric version (SMAST-G); and the AUDIT are often used
with older adults. The MAST-G and SMAST-G were developed specifically for
older adults.
MAST-G and SMAST-G (Table 41-2)
TABLE 41-2 Short Michigan Alcoholism Screening

Test: Geriatric Version (SMAST-G)
Scoring: 2 or more “yes” responses indicative of alcohol problem.
For further information, contact Frederic C. Blow, PhD, at the University of Michigan Department of
Psychiatry, 4250 Plymouth Road, Box 5765, Ann Arbor, MI 48109; (734) 761–2210.
© The Regents of the University of Michigan, 1991.
The MAST-G was developed at the University of Michigan (96) as older adult
alcoholism screening instrument for use in a variety of settings. Psychometric
properties of this instrument are superior to other screening tests. The MAST-G
was the first major elder-specific alcoholism screening measure to be developed
with items unique to older problem drinkers. It relies on a 24-item scale with
good sensitivity and specificity in older adults. Similar values were found after
excluding those subjects who did not currently drink. The SMAST-G is a
validated shortened form of the MAST-G containing only 10 items (Table 41-2).
AUDIT and AUDIT-C (Table 41-3)
TABLE 41-3 Alcohol Use Disorders Identification Test-

C Alcohol Screening (AUDIT-C)
The AUDIT-C is scored on a scale of 0-12 (scores of 0 reflect no alcohol use). A score of 3 or more in
older adults is considered positive and suggests the need for further evaluation. Generally, the higher the
AUDIT-C score, the more likely it is that the patient’s drinking is affecting his/her health and safety.
Dawson DA, Grant BF, Stinson FS, et al. Effectiveness of the derived Alcohol Use Disorders
Identification Test (AUDIT-C) in screening for alcohol use disorders and risk drinking in the U.S. general
population. Alcohol Clin Exp Res. 2005;29(5):844-854, Ref. (98).
The AUDIT is well-validated in adults under 65 in primary care settings

(99–101) and has had initial validation in a study of older adults (7). The AUDIT
comprises two sections: a 10-item scale with alcohol-related information for the
previous year only and a “clinical screening procedure,” which includes a trauma
history and a clinical examination. The questionnaire is introduced by a section
explaining to the respondent that questions about alcohol use in the previous
year only are included. The questionnaire is often used as a screener without the
clinical examination. The recommended cutoff score for the AUDIT has been 8,
but Blow (7) found reliability with good sensitivity and specificity in a sample of
older adults with a cutoff score of 7. A copy of this tool can be found at
http://pubs.niaaa.nih.gov/publications/aa65/AA65.htm. The AUDIT-C (the first
three questions: quantity, frequency, binge) had psychometric properties similar
to the full AUDIT (Table 41-3). Additionally, recent consideration has been
given to using the heavy episodic drinking question alone. Because of the
consequences associated with heavy episodic drinking, it may prove to be a
useful and important question that can stand alone.
Broad-Based Assessment
Clinicians can follow up the brief questions about consumption and
consequences such as those in the MAST-G and AUDIT, with a few more in-
depth questions about consequences, health risks, and social/family issues. To
assess AUD, questions should be asked about alcohol- or drug-related problems,
a history of failed attempts to stop or cut back, or withdrawal symptoms such as
tremors. Clinicians should refer patients thought to meet criteria for AUD for a
diagnostic evaluation and possible brief or formal specialized treatment.
Medication assessments include questions about prescriptions, particularly
antidepressants, benzodiazepines, opioid pain medications, OTC medications,
and herbal remedies. If there is evidence of a prescription drug use disorder, the
patient should also be referred to a specialist to obtain further assessment. For
older adults with SUD symptoms, assessments are needed to confirm the
problem, to characterize the dimensions of the problem, and to develop
individualized treatment plans. For insurance reimbursement purposes, the
assessment should follow criteria in the DSM or other relevant criteria, keeping
in mind that these criteria may not apply directly to planning older adults’
treatment.
The use of validated SUD assessment instruments can be of great help to
clinicians by providing a structured approach to the assessment process as well
as a checklist of items that should be evaluated with each older adult.
Specialized assessments are generally conducted by substance treatment
program personnel or trained mental and physical healthcare providers.
Structured assessment interviews “possess (at least potentially) the desired
qualities of quantifiability, reliability, validity, standardization, and
recordability.”
Despite limitations with criteria used to assess older adults (97), a general
psychiatry structured assessment instrument that has been widely used over
many years is the Structured Clinical Interview for DSM-III-R (SCID) (102). It
takes a trained clinician ~30 minutes to administer the 35 SCID questions that
probe for an AUD.
Laboratory Tests
Although self-report is the primary tool used to assess alcohol consumption,
biological markers for alcohol use may be useful for physicians. Such tests can
be used to identify current alcohol consumption status, facilitate discussions with
patients about adverse health outcomes associated with their alcohol intake, as
well as provide prognostic information for follow-up. For more information
about biomarkers to detect or monitor alcohol use, see publications from
Dasgupta and Cabezas (103,104).
Alcohol biomarkers have their pros and cons and should be interpreted with
caution (104). Direct alcohol biomarkers, tests that detect ethanol in the breath,
urine, serum, or bodily fluids, are the gold standard of alcohol detection, but test
only recent intake. Indirect biomarkers obtained from a complete blood count
such as alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio
and gamma-glutamyltransferase (GGT) are all liver function tests that are
inexpensive and widely available. Carbohydrate-deficient transferrin (CDT) has
been widely used as a marker of heavy alcohol use, but has a high rate of false
negatives. Macrocytosis, an increase in mean corpuscular volume (MCV) of red
blood cell size, in older adults often suggests high levels of alcohol consumption,
since it increases with chronic alcohol intake of 80 g of alcohol per day.
However, there are secondary causes of a high MCV, such as folate and/or B12
deficiency, liver problems, hypothyroidism, the use of certain medications, and
myelodysplastic syndrome (105).
Indirect alcohol biomarkers that are used to detect ethanol metabolites are
also used to detect alcohol consumption. Metabolites such as CDT, fatty acid
ethyl esters (FAEE), phosphatidylethanol (PEth), and ethyl glucuronide (EtG)
can be measured in blood, urine, or hair and have been shown to measure
alcohol consumption anywhere from days to up to several months of use,
depending on the test. However, confounders such as gender, age, and health
status may affect test results (106).
INTERVENTION STRATEGIES FOR
OLDER ADULTS
Brief Alcohol Interventions
There is a large body of research testing brief motivational interventions in a
variety of healthcare and social service settings. Brief interventions have had the
most success across age groups and over time in primary care settings. Whitlock
et al. (107) conducted a meta-analysis and examined 39 studies; 12 met criteria
for inclusive review and found that randomized clinical trials in primary care
were efficacious; and Havard et al. (108) examined randomized clinical trials in
the emergency care settings.
Studies have shown that older adults can be engaged in brief intervention
protocols. Such protocols are acceptable in this population; and, there is a
substantial reduction in drinking among the at-risk drinkers receiving the
interventions compared with a control group (47,109–111). Moore et al. (31)
conducted a trial to examine whether an intervention among older at-risk
drinking primary care patients reduces alcohol consumption and at-risk drinking
at 3 and 12 months. They randomized 631 participants over 55 years of age who
were at-risk drinkers. At 12 months, alcohol consumption was less in the
intervention compared to the control group (9.27 vs. 10.71 drinks per week).
Even with statistically significant differences between groups, the actual
differences are not large and there are limits in the effect over time. At 3 months,
46% of intervention versus 61.21% control participants were at-risk drinkers; at
12 months, 53.87% of intervention versus 60.38% of controls were at-risk
drinkers. It is important to note that there were limits in the effect over time.
Project SHARE (Senior Health and Alcohol Risk Education) (111) was a
cluster-randomized controlled trial of 31 primary care providers and their
patients aged 60 years older. Study physicians and their patients were randomly
assigned to usual care (n = 640 patients) versus the Project SHARE intervention
(n = 546 patients), which included personalized reports, educational materials,
drinking diaries, physician advice during office visits, and telephone counseling
delivered by a health educator. At 12 months, the intervention compared to the
control was significantly associated with an increase in alcohol-related
discussions with physicians (23% vs. 13%; p ≤ 0.01) and reductions in at-risk
drinking (56% vs. 67%; p ≤ 0.01), alcohol consumption (−2.19 drinks per week;
p ≤ 0.01), physician visits (−1.14 visits; p ≤ 0.03), emergency department visits
(16% vs. 25%; p ≤ 0.01), and nonprofessional caregiving visits (12% vs. 17%; p
≤ 0.01). In general, brief interventions with older adults have seen statistically
significant changes in alcohol use, but the actual number differences are small.
This could, in part, be that older adults in primary care studies, in particular, are
at-risk drinkers and not harmful drinkers. Those with harmful drinking patterns
generally require continuity of care sand support to maintain changes.
FORMAL ADDICTION TREATMENT IN

OLDER ADULTHOOD
Medication Interventions
Although unhealthy alcohol use is a significant and growing health problem in
the United States, there have been few systematic studies of formal treatment
outcomes for older adults. Because traditional residential SUD treatment
programs provide services to very few older individuals, sample sizes for
treatment outcome studies have often been inadequate (112). Naltrexone and
acamprosate have been approved for treatment of DSM-IV–defined alcohol
dependence and have shown to improve alcohol consumption outcomes (113).
However, these treatments are underutilized in the treatment of older adults with
AUD.
Naltrexone, an opioid antagonist, reduces craving for alcohol and decreases
the rate of relapse to heavy drinking. It has demonstrated efficacy in large
samples that have included older adults and in studies of older adults exclusively
(114,115). However, in a multicenter, double-blind, placebo-controlled
evaluation of veterans (mean age 49), Krystal et al. (116) found no significant
differences in percentage of days drinking and drinks per day at 52-week follow-
up. One of the few studies testing naltrexone (50 mg/d) in older adults was
conducted by Oslin et al. (117), who enrolled 44 veterans older than age 50 in a
12-week double-blind placebo-control efficacy trial. There were no significant
differences between the groups in abstinence, but half as many subjects in the
treatment group lapsed into significant drinking compared to the control group.
Naltrexone was well-tolerated by older adults and had efficacy in preventing
relapse. However, naltrexone, because it is an opioid blocker, cannot be used in
patients who require opioid analgesics; adding naltrexone to the regimen of a
patient on opioid analgesics may provoke significant opioid withdrawal
symptoms.
Acamprosate has also been approved as an agent in the treatment of DSM-
IV–defined alcohol dependence (118,119). There is mixed clinical evidence for
the use of acamprosate (120). The COMBINE study was a large trial in which
eight groups of patients received medical management with 16 weeks of
naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with
or without a combined behavioral intervention (CBI). A ninth group received
CBI only (no medication). Patients were also evaluated for up to 1 year after
treatment. In this trial, acamprosate showed no significant effect on drinking
when compared to placebo, either by itself or with any combination of
naltrexone, a CBI, or both. To date, there are no studies of the efficacy or safety
of acamprosate with older patients.
Formal Specialized Treatments

Because traditional residential SUD treatment programs generally provide
services to few older adults, there have been few studies with large enough
populations of older adults to determine the effectiveness of residential
programming in this age group. There are a few naturalistic studies suggesting
that older adults who do engage in treatment have better outcomes compared
with younger adults (112,121–123). Older adults also seem to do best in
programs that offer age-appropriate care with providers who are knowledgeable
about aging issues (121,124). A number of the studies of midlife to older adult
treatments have been conducted in the VA setting.
One of the few randomized controlled trials of treatment outcomes for older
adults is a study of 137 male veterans (age 45-59 years, n = 64; age 60-69 years,
n = 62; age 70 years and older, n = 11) with DSM-IV–defined alcohol
dependence who were randomly assigned after withdrawal management to age-
specific treatment or standard mixed-age treatment (125). Outcome data showed
that those in the age-specific treatment programs were 2.1 times more likely at 1
year to report abstinence compared with patients in mixed-age groups. Because
baseline alcohol consumption and alcohol severity data were not collected as
part of the study, baseline data could not be compared for those variables.
D’Agostino and colleagues (126) created a model community-based
intervention program, the Geriatric Addictions Program (GAP), designed to
assist older adults who have SUDs and co-occurring mental health problems in
accessing services and changing health behaviors. 120 older adults were
randomly assigned into a traditional referral approach with an assessment and
linkage model or a multidimensional approach incorporating geriatric care
management assessment, motivational counseling, and the combination of aging
service and addiction treatment linkages. Outcome data showed that those in the
second group, with the multidimensional approach, had greater rates of linkage
to both outpatient and inpatient treatments.
Most of the treatment outcome research on older adults with SUDs has
focused on compliance with treatment program expectations, in particular the
patient’s fulfillment of prescribed treatment activities and goals, including
drinking behavior. Results from compliance studies have shown that age-specific
programming improved treatment completion and resulted in higher rates of
attendance at group meetings compared to mixed-age treatment (127). In
addition, older adults with SUDs were significantly more likely to complete
treatment than younger patients. Atkinson et al. (128) also found that the
proportion of older male DSM-IV–defined alcohol-dependent patients
completing treatment was twice that of younger men.
In a more recent study (129), older patients were compared with matched
groups of younger and middle-aged patients in inpatient alcohol treatment
programs (n = 432 in each age group). Compared with other patients, older
patients had poorer physical health and lower cognitive status at treatment entry,
but they were drinking less and reported fewer drinking-related problems, fewer
psychological symptoms, more social support, more adaptive coping, and fewer
barriers to abstinence. At discharge, older patients showed significant change in
most areas targeted for treatment. The age groups showed similar outcomes,
prognostic factors, and response to different treatment orientations.
Studies on the effect of age of onset on treatment compliance have yielded
mixed results. Major limitations remain in the treatment compliance literature,
including a lack of drinking outcome data, failure to report on treatment
dropouts, and variations in definitions of treatment completion. In addition, there
have been fewer recent studies that have focused on older adults in treatment
settings than were conducted in the 1990s. More carefully controlled,
prospective treatment outcome studies that include sufficiently large numbers of
older subjects who meet criteria for alcohol dependence are needed to address
the methodologic limitations of prior work.
LIMITATIONS OF TREATMENT
OUTCOME RESEARCH
Although the examination of factors related to completion of programming is
important for the identification of patient characteristics for those who will
remain in treatment, existing studies have an inherent selectivity bias and
provide no information on treatment dropouts or on short- or long-term
treatment outcomes. Other issues with sampling may also limit the
generalizability of previous studies. For example, the majority of reports on
alcoholism treatment outcome for older adults have included only male subjects.
Furthermore, age cutoffs for inclusion in studies have varied widely and have
included individuals at midlife in the “older” category. In addition to these
issues, the majority of studies have used relatively unstructured techniques for
assessing alcohol-related symptoms and consequences of drinking behavior.
Finally, the manner in which outcomes have been assessed has been narrow in
focus. Most studies have dichotomized treatment outcome (abstention vs.
relapse) based solely on drinking behavior. A number of studies have taken place
in VA treatment facilities limiting generalizability to the general population and
to women.
Given evidence that heavy or binge drinking is more strongly related to
alcohol consequences than is average alcohol consumption, it is possible that
there are important differences in outcome for nonabstinent individuals,
depending on whether their reuse of alcohol after treatment involves binge
drinking. Furthermore, most studies have not addressed other relevant domains
that may be positively affected by treatment, such as physical and mental health
status, and psychological distress.
Relapse Reduction
Individual Relapse Reduction
Older adults have age-related risks for relapse that need to be considered.
Barrick and Connors (115) reviewed the literature regarding relapse reduction
among older adults with AUDs and highlighted how psychosocial factors such
as social isolation, loneliness, loss and grief, and depression can become
antecedents to alcohol use and how older drinkers tend to report using alcohol to
alleviate negative emotional states.
Comorbid medical conditions also put older adults at higher risk for relapse.
For example, Brennan et al. (68) studied the relationship of alcohol use and pain
among older adults. They found that more pain was related to increased use of
alcohol to manage pain and that this relationship was stronger for older adults
with drinking problems than for those who did not have problems with alcohol
use. Barrick and Connors (115) summarize the types of relapse reduction
treatment approaches such as cognitive behavioral therapy, group and family
therapies, self-help groups, and pharmacological adjuncts; and, they provide
useful information for the development of appropriate clinical relapse prevention
models.
CONCLUSION
Because of the complexity of medical and psychosocial intervention and
treatment issues, older adults who are experiencing problems related to the use
of alcohol, prescription medications, and/or other drugs present unique
challenges to the healthcare system. Fortunately, there are a number of venues in
which to detect substance-related problems in older adults, including primary
care clinics, specialty care settings, home health care, elder housing, and senior
center programs. Strategies for working with older adults who are using alcohol
and/or prescription medications/drugs at risk levels such as minimal advice,
structured brief intervention protocols, formalized treatment for older persons
with AUDs, and specialized relapse prevention programs provide useful tools to
begin to address this growing issue. Both from a public health standpoint and
from a clinical perspective, with the aging of the baby boom cohort, there is a
critical need to implement effective screening and intervention strategies with
older drinkers who are at risk for more serious health, social, and emotional
problems.
An emerging issue that will need to be addressed in healthcare delivery to
aging population is their use of alcohol and/or medications and other drugs. This
will often need to be done in the context of healthcare settings where providers
are expected to deliver quality medical care for a wide variety of health
problems within greater time constraints. Therefore, the development of short,
effective techniques to address substance use issues in the growing population of
older adults continues to be an important focus for the alcohol and drug field.
Evidence-based innovative screening, intervention, and treatment methods for
alcohol and drug use among older adults have been developed and tested in a
number of settings that serve this population. If successfully implemented, the
evidence-based screening techniques, brief interventions, and brief treatments
will be key steps in the process of assuring that current and future generations
have the opportunity for improved physical and emotional health. The challenge
to the system will be moving from the development of these evidence-based
programs to actually implementing them in the real world—the “bench to
bedside” dilemma.
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CHAPTER 42
Cultural Issues in Addiction Medicine
Joseph Westermeyer and Patricia Jean Dickmann
CHAPTER OUTLINE
Introduction
Cultural Definitions Related to Substance Use
Culture and Patterns of Substance Use
Cultural Aspects of Clinical Assessment
Substance and Gambling-Specific History
Addiction and Patients’ Cultural Function
Culture, Treatment, and Recovery
Conclusions
INTRODUCTION
This chapter endeavors to help clinicians incorporate cultural factors when
treating substance use disorders. This involves cultural aspects of assessment as
well as treatment. To acquire and utilize this information, the clinician should
know how cultural factors can potentially serve as pathogenic agents or
therapeutic resources. Acquiring the necessary clinical knowledge, attitudes, and
skills depends on learning several sociocultural concepts relevant to substance
use. Clinicians who know and can apply these concepts possess “clinical cultural
competence,” which facilitates clinicians in engaging, retaining, and fostering
optimal clinical outcomes among culturally diverse patients. The clinical goal is
to enable the patient to return to health, psychological competence, and full
sociocultural function.
Substance use disorders can vary widely across nations and cultures. For
example, high rates of alcohol use disorders occur in several countries of Eastern
Europe, especially Hungary, Poland, and Romania (1); the Australian aborigines
(2); and the Northern Plains tribes of North America (3). Likewise, ethnic groups
in Southeast Asia that raise poppy as a cash crop (eg, Hmong and Iu Mien) have
high rates of opioid use disorder (4). At times, subgroups within a culture can
manifest high rates. For example, nearly two out of three college students in the
United States report an episode of heavy episodic drinking (a high-risk drinking
pattern characterized by five drinks or more for men, four drinks or more for
women) in the last 2 weeks (5), a 20% increase over a decade (6). Social
disruption and armed conflict can lead to widespread addiction, as occurred in
northeastern Afghanistan during the 1990s (7). Some nations have notably
reduced the prevalence of addiction, exemplified by less opium and heroin use
disorder in China during the last half century (8).
Many national governments are devoting more attention to culture and
health services, including addiction care. In the United States, for example, the
National Standards for Culturally and Linguistically Appropriate Services
(CLAS Standards) aim to improve healthcare quality, efficacy, equity, and
respect for each patient in this increasingly diverse country (9). The National
CLAS Standards provide a framework for enhancing culture and language
appropriate policies, legislation, communication, and continuous improvement
activities. The pillars of CLAS encompass respect and responsiveness, that is,
respecting the individual and responding to each individual’s health needs and
preferences (10).
This chapter highlights cultural factors influencing the prevalence of
substance use disorders across nations and cultures, plus the importance of
providing culturally competent care to reduce health disparities and achieve
health equity. Our objectives include:
describing linkages joining culture and addiction

describing clinical skills needed to take a substance use history and inquire
about each patient’s unique cultural characteristics
articulating therapeutic attitudes that can serve people across cultures (11)
CULTURAL DEFINITIONS RELATED TO

SUBSTANCE USE
Several concepts can aid clinicians in perceiving how culture may contribute to,
or alleviate substance use disorder (see Table 42-1 for a list of these terms).
Cultures typically have laws and traditions regarding substance production,
distribution, and consumption. Most nations encompass numerous cultures, or
ethnicities. Within a nation, ethnic groups can differ greatly in their use of
alcohol and other psychoactive substances. Their attitudes, values, and practices
toward substances may resemble or differ from those of the culture at large (12).
TABLE 42-1 Definition of Culture-Related Terms with

Utility in Understanding, Assessing, and Treating
Substance Use Disorder and Gambling Disorder
Groups of people with substance use disorder can comprise subcultures with
their own values, loyalties, beliefs, and traditions. Examples include a
neighborhood tavern, crack house, or college party house (13). Although
subcultures can furnish environments for the spread of addiction, recovery
subcultures can impart settings to escape addiction. Affiliating with Alcoholics
Anonymous, Narcotics Anonymous, and Smart Recovery can reinforce healthy
norms and reduce relapse risk.
An ideal norm might prescribe use of a substance under certain
circumstances, such as drinking wine during Jewish Passover or consuming
peyote in the Native American Church. Or, an ideal norm may demand
abstinence, such as abstention from alcohol by many Muslim sects, or from
tobacco by Seventh-Day Adventists. Behavioral norms consist of what people
actually do (14). A norm gap or conflict occurs if the ideal norm and behavioral
norm diverge. In cultures with norm conflicts regarding substance use, substance
use disorders predictably ensue (15). Bringing norm dissonance to patients’
awareness can aid the journey to a culturally syntonic recovery.
Exploring the individual’s cultural identity can lead to valuable insights that
can guide interventions during motivational interviewing. For example, when
asked about his or her identity, one patient replied, “I’m what you might call a
common drunk, doc, but I’m not an alcoholic.” This response led to a useful
conversation regarding the patient’s criteria for these categories and why he or
she was willing, even anxious, to accept one identity while vehemently rejecting
the other. Entrenched negative and stigmatizing language and identities (eg,
“common drunk” and “pothead”) can serve as a justification for continued
addiction (16).
CULTURE AND PATTERNS OF

SUBSTANCE USE
When ideal and behavioral norms regarding substance use are matched up,
substance use rarely exists. On the other hand, groups that prohibit use of a
substance in theory and yet foster its use in practice invite individuals to decide
on their own use pattern. This latter circumstance results in some people
abstaining, others using moderately, and vulnerable people using heavily. Recent
examples of norm conflict fostering increased substance use in the United States
include marijuana laws and socially prescribed patterns of use (17), widespread,
excessive opioid prescribing for chronic pain (18), and college binge drinking
(5). Table 42-2 shows the concomitants of substance use in association with
norm conflicts (19).
TABLE 42-2 Consequences of Substance Use

Depending on Presence Versus Absence of Norm
Conflict
Despite similarities and differences among cultural groups (20), clinicians must
assess each patient as a unique individual who may differ from others in the
group. Stereotyping patients is never warranted, as relying on general trends can
be clinically misleading:
Within any large population, considerable differences can exist among

subgroups. For example, Korean Americans tend to have higher rates of
substance use disorders than other Asian American groups (21).
Rates of substance use disorder may change with the generations since
immigration. For example, Mexican American women have extremely low
rates of substance use disorder in the first generation after immigration, but
rates comparable to other American women in the second and subsequent
generations (22).
Sociocultural changes within ethnic groups can affect the pattern of
substance use and disorder over time. For example, some Hispanic
Americans have abandoned Roman Catholicism for abstinence-oriented
Protestantism in an effort to resolve alcohol use disorder (23). The Hmong,
an Asian American immigrant group, formerly had no norm gap with
regard to alcohol use and virtually no alcohol use disorder. However,
widespread conversion to abstinence-oriented Protestantism resulted in a
norm conflict regarding drinking and the appearance of alcohol use disorder
(24).
Clinicians must conduct individual assessments for each new patient while
avoiding stereotyping. Failure to do so results in both missed diagnosis (in
patients from groups with low rates of substance use disorder) and erroneous
overdiagnosis (in patients from groups with high rates of substance use
disorder).
CULTURAL ASPECTS OF CLINICAL

ASSESSMENT
Taking a Cultural History

The first step in conducting a cultural history consists of asking the patient about
the ethnic origins of his or her parents and grandparents, or their surrogates.
Relevant information includes his/her place of birth, national origin, language
learned at home, migrations, roles and affiliations in the ethnic community, and
roles and affiliations in the community at large. Educational experiences or
marital history may be relevant, depending on the case. The second step consists
of assessing the family’s overall enculturation of the patient into his or her ethnic
groups of origin (25). Was one or more of the parenting adults actively using
substances during the patient’s childhood? Parental substance use disorder can
disrupt a health identity formation and undermine cultural competence (26).
Inability to work, play, and develop meaningful relationships increases the risk
of addiction (27).
Adapting to life in an unfamiliar culture can involve stressors that may
precipitate unhealthy substance use (28). During late adolescence and early
adulthood, relocation to college, the military, or a cross-ethnic marriage can alter
previously learned substance use norms (29). Even optimal environmental
conditions in adoptive or foster home placement do not eliminate the increased
genetic risk acquired from biological parents (30).
SUBSTANCE AND GAMBLING-SPECIFIC

HISTORY
Cultural groups ensocialize young people in psychoactive substance using, or
gambling, specific methods. Inquiry into these methods can help both the patient
and the clinician in understanding the patient’s earlier decisions regarding
substance use or gambling, as follows:
Observations of role models: What substances or gambling-related

behaviors did the parenting adults use in the home or outside of the home?
Was the use unhealthy, associated with problems, or disruptive to the
family?
Socialization into psychoactive substance use: Who first guided the
patient’s use of psychoactive substances or gambling? Did this occur in the
home with family or outside with peers? What substances, gambling, and
modeling did their mentors provide? How old was the patient at the time?
Early experience with substances or gambling: Were these mentors people
who used substances or gambling themselves? How did early use assist
coping in the family, at school or work, or while dating?
Association with other developmental tasks: Was the patient learning other
developmental tasks at the same time? These other developmental tasks
might include acquisition of social skills, early sexual experiences, or
managing emotions.
ADDICTION AND PATIENTS’ CULTURAL

FUNCTION
Psychoactive substance use may foster social coping, at least initially. For
example, use of stimulants may contribute to studying, athletics, working, or
functioning despite lack of sleep. Once addiction ensues, drugs that earlier
enhanced performance begin to undermine it.
Young people may use substances to benefit acquiring social competence.
An 19th century example involved taking the anticholinergic herb belladonna
(meaning “beautiful lady”) to produce rosy cheeks and a healthy appearance.
Similarly, ecstasy and gamma hydroxybutyrate (GHB), sometimes referred to as
club drugs, appear to foster sociability, feelings of acceptance, and transient
intimacy.
Initial doses may fail to relieve anxiety as time passes for some people.
Gambling may be used as a means of escape (common in females) or as a means
to achieve a sense of power, mastery, or control (common in males). Sustaining
symptom relief may require higher doses over time, as in the following case:
A college freshman found that one drink before attending a party alleviated
her severe anxiety about socializing with new people. By her junior year, she
required several drinks to achieve the same effect as formerly achieved with one
or two drinks. Consequently, she was showing up intoxicated at social events.
This led to an intervention by her peers, who had become alarmed at her drunken
behavior. She sought a professional opinion, complied with treatment
recommendations, and was successfully treated for social phobia. Abstinence
was recommended in view of her propensity to anxiety disorders, her family
history of substance use disorder, and her own escalation to unhealthy alcohol
use. She joined an abstinence-oriented recovery group on her college campus.
Achievement of a certain social status followed by its loss appears may herald a
substance use disorder (19). Examples include the following:
Marital status: separation, divorce, repeated failed marriages, and liaisons

of ever-shorter duration
Employment status: jobs of ever-more-brief duration at statuses below one’s
training or education, longer durations of unemployment, and losing jobs
from working under the influence of substances
Housing: living with others who use substances, living in institutional
settings (eg, halfway houses and shelters), ending up homelessness
Community participation: avoiding sober groups, events, and activities
Social network: an increasing percentage use substances heavily
Legal problems: breaking laws related to driving under the influence of
alcohol or drugs, drug possession or sale, property law offenses, and
violence
Financial problems: inability to pay bills, selling property to buy substances
or to gamble, bankruptcy, scamming, or stealing
Addiction subcultures may welcome new members estranged from family and
other groups. These subcultures do not impose hurdles of the kind that
distinguish career advancement, achievement in sports, or efforts invested in
family or community. Thus, young people who have failed to achieve cultural
competence may drift toward substance-focused subcultures—recognized in
Alcoholics Anonymous tradition as “consorting with lower company.”
CULTURE, TREATMENT, AND

RECOVERY
Addiction, Recovery, and the Intimate Social

Network
The normal “intimate social network (ISN)” of one person (or “proband”)
consists of 20-30 people organized into four or five groups (31) (see Table 42-3).
Typical subgroups include the face-to-face living groups, relatives, friends,
coworkers, and perhaps another group or two (eg, neighbors, association
members, church, or recreational group). The chance that any one person knows
another in the proband’s ISN (termed “connectedness”) is about 80%. Such
groups tend to be stable over time. If a proband and another ISN member
become estranged, their group fosters rapprochement. In this way, the ISN
promotes the settling of inevitable interpersonal conflicts, thereby enhancing
maturation, intimacy, and trust over time. ISN relationships are also reciprocal.
The proband exchanges work, time, or resources with other ISN members.
Exchanges necessarily limit ISN size to around 20-30 people (rarely more than
40). Middle-class, middle-aged, married, employed men with alcohol use
disorder were noted to have normal ISN size upon entering addiction treatment
(32). However, they lost about half of their ISN members (mostly other heavy
drinkers) during early recovery, precipitating feelings of loss, loneliness, and
lack of support.
TABLE 42-3 Characteristics of the Intimate Social

Network in Relation to Clinical Characteristics
aLikelihood that any one person in the intimate social network (ISN) knows anyone else in the ISN.
Progressive addiction and growing dysfunction reduce the ISN to <20 people,
with two or three groups (eg, family and relatives) plus some one-to-one
relationships. The “connectedness” of the ISN tends to be less, about 60%, with
recent one-to-one relationships. Although the element of reciprocity persists, the
proband may become more of a client vis-a-vis other people in the ISN. The
latter may consist of drug dealers, bartenders, hair stylists, clergy, social
workers, and health professionals. These patients sometimes report ISN
members not ordinarily reported, such as deceased persons, pets, or people who
were close friends years ago (33).
With disability, the ISN declines further to 10 or fewer people, most of
whom know one another only through the proband. Their common link involves
nonreciprocal relationships with the proband, who takes but seldom returns their
courtesies. For example, a parent, social worker, homeless shelter manager, and
policeman may all know one another through their respective efforts to help the
proband. Eventually, the alienated proband may become isolated to the point of
not having anyone to call upon—a grave prognostic sign (34).
ISN reconstruction offers a potent means for intervening in the addiction
process and supporting recovery (35). A key element involves eliminating
companions who use drug companions from the ISN, with retention of those
committed to the patient’s ultimate recovery (36). This approach has proven
useful even in cases with limited family or economic resources (37). Sober
communities, halfway houses, and shelters depend on this powerful strategy.
With sobriety and sufficient time, those who are employed, living within a
family, and supported by peers can rebuild a functional, supportive ISN, as in the
following case:
A surgeon referred a veteran who reported that the preoperative sedative
provided him with the first full night of sleep that he had experienced in years.
The patient, in for surgical repairs related to shrapnel injuries, had been seriously
wounded in combat, with polytrauma and blast injury. After his return to civilian
life, he completed postcollege professional training. Despite his many successes,
he went to his basement once or twice a month to drink a quart of whiskey alone
and think about his experiences and deceased comrades-in-arms. Aside from his
spouse and two children, he had minimal social contacts or commitments outside
of his professional work. Evaluation revealed chronic posttraumatic stress
disorder and alcohol use disorder. After a 3-month period of sobriety and good
relief from his posttraumatic stress disorder and insomnia, he began
reconstructing his ISN. He chose first to expand his affiliations with his former
combat unit. This choice provided opportunities to obtain support from those
with similar experiences and, eventually, to provide support to others (similar to
the role of sponsors in Alcoholics Anonymous). A few years later, he became
active with the alumni group where he received his professional training,
providing him with opportunities to “pay back” that institution. This gradual
process required over a decade.
This case demonstrates principles of ISN reconstruction. First, the patient had a
period of sobriety and psychological recovery from his alcohol disorder and
posttraumatic stress disorder before initiating a process that could be stressful
and result in rejection or failure. Second, he chose to join a sequence of identity
groups (veterans first, alumni second, and ethnic group third), starting with the
group that would accept him without excessive demands and ending with the
group that he felt would be most challenging. He believed (and rightly, as it
turned out) that his veteran group would accept him whatever his circumstances,
given their shared combat experience and injuries.
Cultural Recovery in Substance Use

Disorders
Reconstruction of the ISN poses a serious challenge. Most people have a full
complement of people with whom they have stable relationships. Thus, they do
not readily take on another person outside of their current ISN. Nonetheless, a
number of strategies have proven useful ISN reconstruction during recovery, as
follows:
Joining a recovery group whose members are also looking for new
associates (eg, Alcoholics Anonymous, Narcotics Anonymous, and Smart
Recovery)
Participating in a sports or exercise club, or occupational association
Supporting a charitable organization or social group with a charitable
purpose
Volunteering at a school, clinic, hospital, or nursing home
Returning to an ethnic association or church group
Taking a job (part time or full time) that leads to new contacts
These strategies replace the groups associated with psychoactive substance use
in the person’s previous life (38). They lead to affiliations with new people and
groups, affording the recovering person new opportunities for success.
A more difficult task can occur in building bridges back to relatives and
family members. Previous addiction-related affronts may have alienated them.
Relatives and family members need evidence that the recovering person can
follow through on commitments, engage in reciprocal acts of mutual support,
and adopt a predictable lifestyle. Accordingly, it may be wise to delay rebuilding
certain relationships until a modicum of sobriety (ie, 6-24 months) has been
established. If the recovering person suffers slips or recurrences—common in the
early months or recovery—this can reaffirm the family’s worst fears. Awash with
renewed negative expectations, after an initial spurt of hope and optimism,
family members may become ever more entrenched in their wariness.
Fortunately for those involved in a 12-step recovery, several early steps prepare
the recovering person for making amends to outraged family and former friends.
Resuming affiliations can give rise to emotionally warm and spiritually
uplifting experiences. Such a social or cultural “rebirth” can feel like a second
chance, a turning back the clock, and a visit back to familiar places and habits.
This experience can elicit feelings of acceptance, belonging, and positive
identity. By the same token, these journeys back can be suffused with pain,
regret, shame, and guilt. Fortunately, positive encounters seem to outnumber
negative ones for most people. Total rejection can encourage affiliations in a new
religion or new cultural identity.
Computer-based social networks comprise an increasingly popular means for
recovering people to join with like-minded people, chat on social media, play
competitive games, acquire information, begin new relationships, and even
attend mutual-help groups. However, overuse, risky use, or too trusting use of
the Internet may lead to problems that precipitate relapse (39). A lonely person
might buy into the illusion of real relationships, which turn out to be Internet
fictions (avatars). Having 1000+ “friends” on Facebook cannot mimic the
commitment, continuity, and reciprocity existing within one’s real-life ISN.
Evolution of Sociocultural Interventions
Sociocultural therapies outside of traditional clinics and hospitals have evolved
over decades and centuries, as individuals, communities, clinicians, and
researchers grapple with the lengthy duration and extensive rehabilitation
necessary for recovery. Some of these interventions survive and are exported
internationally, for example, mutual help groups (from 19 Century England), day
hospitals (from WWII Moscow), and workplace programs (from former
Yugoslavia). Other innovations wane in one place and flourish elsewhere, for
example, the decline of addiction-focused therapeutic communities (in the
United States) and their resurgence in the Malay Archipelago.
As a current example in North America, the “Housing First” model has
gained popularity and serves hundreds of thousands of individuals with
substance use disorders. This model involves first providing “permanent
independent housing” to homeless, people with addiction, then following up
with optional addiction treatment services. Some studies suggest that “Housing
First” is a significant cost-saving panacea, and others indicate that it simply
shifts costs and increases morbidity and mortality (40–44).
Culture-Specific Treatment
Therapies specific to particular cultures can contribute to recovery from
substance use disorders. Participation aids the recovering person in several ways:
providing a sober environment, engaging in meaningful work, receiving
emotional support from others, and building a new identity as a recovering
person.
Some of these interventions are ceremonial in nature, symbolizing a spiritual
rebirth, a successful healing, or a long period of sobriety. See Box 42-1 for a
précis regarding the Native American Church (sometimes referred to as Peyote
Religion), a dynamic institution with roots in Native American religious practice
and Christian practices and concepts.
BOX 42-1
THE NATIVE AMERICAN CHURCH (PEYOTE
RELIGION)—A PRECIS
The Native American Church, also known as Peyotism or Peyote Religion, is a
religion characterized by a combination of traditional Native American beliefs,
Christian beliefs, and ceremonial use of peyote. Many adherents have sought
ministrations and solace in the church as a means of addressing cultural
anomie, alcohol use disorder, and other maladies. There are an estimated 250
000 members, including 40 American Indian tribes, in the United States,
Canada, and Mexico as of the late 20th century (45). Peyote, harvested from a
cactus flower found in Texas and Mexico, is thought to enable the consumer to
communicate with God, spirits, and portals to reality. It is believed that
consuming peyote brings spiritual powers, centeredness, healing, and guidance
(46). Peyote’s active ingredient, mescaline, can produce colorful visual
hallucinations and insomnia with psychogenic effects lasting a few hours to 3
days, with an average duration of 10-12 hours. There is one case study
documenting peyote-induced psychosis and insomnia lasting 2 weeks (47).
The all-night peyote ritual typically takes place in and around a tepee and
includes prayer, singing, dancing, and consumption of peyote, sometimes
ending the next morning in a feast to which family or friends may be invited.
Although peyote was banned by government agents and 15 states in the late
1800s through the mid-1900s, Congress, the Bureau of Indian Affairs, the
Native American Church, and some Native American groups resisted in the
name of constitutional freedom of religion (48). Since 1965, Federal
regulations have protected the ceremonial use of peyote by Native Americans.
The American Indian Religious Freedom Act of 1978 was amended in 1994 to
provide for the traditional use of peyote by Native Americans for ceremonial
purposes (49).
Referral to treatment that undermines positive cultural or ethnic values or that

introduces unacceptable risks can be counterproductive. For example, some
people may dislike the “higher power” emphasis in Alcoholics Anonymous but
accept the biosocial paradigms in Smart Recovery. Many ethnic groups find
group sweats relaxing and supportive, but they can pose a risk if the patient is
still in withdrawal or has cardiovascular problems.
CONCLUSIONS
Substance use and gambling are much more important in most cultures to be left
to individual judgments and decisions. Across history, cultural groups have
fostered specific norms with regard to substance use and gambling. Social
dissensions regarding tobacco, alcohol, and cannabis use aim fundamentally at
evolving a common cultural consensus—not an easy task in a highly diverse
culture that values individuality.
Clinicians can increase their effectiveness by inquiring about the cultural
elements that accompany the patient into the consultation room. This task begins
with understanding patients’ enculturation experiences into substance use from
childhood to adulthood. Our patients’ current and past cultural affiliations can
help in devising successful recovery plans. Assessing the patient’s ISN can
instruct us on the severity of the disorder, therapeutic resources readily at hand,
and formulation of realistic treatment goals. As cultural factors have contributed
to the onset of substance use or/and gambling disorder, likewise cultural
resources and traditions can aid clinicians and patients in the challenging process
of recovery.
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CHAPTER 43
College Student Drinking
Frank J. Schwebel, Ursula Whiteside, Joyce N. Bittinger,
Jason R. Kilmer, Ty W. Lostutter, Mary E. Larimer
CHAPTER OUTLINE
Prevalence and Consequences
Prevention Strategies and Interventions
Conclusions and Future Directions
PREVALENCE AND CONSEQUENCES

Heavy drinking and significant alcohol-related problems impact college students
nationwide (1). An estimated 1825 college student deaths annually between
1998 and 2005 involved alcohol (2). Heavy episodic (or binge) drinking and the
detrimental consequences resulting from this type of drinking have led the U.S.
Department of Health and Human Services and the Surgeon General to classify
college student binge drinking as a major public health problem. Though
extensive research and administrative efforts have been aimed at decreasing
college student binge drinking, problems and consequences such as driving
under the influence, academic and relationship consequences, and student deaths
due to alcohol-related injuries and suicide continue to occur at relatively high
rates (2). What follows is a review of the research on college student drinking
including prevalence rates and consequences, risk factors for college drinking,
and a discussion of empirically supported interventions and treatment practices.
Drinking Rates and Disorders Among College

Students
Reports indicate that approximately four out of five (81%) college students have
consumed alcohol and 68% have been drunk at least once in their lives (3).
When examining only the past month, 38% reported having been drunk and 3%
reported drinking daily, while 31% have engaged in heavy episodic drinking
(defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA)
as reaching a blood alcohol level of 0.08 or higher, usually by consuming five or
more drinks for men and four or more for women, over a 2-hour period) in the
past 2 weeks (1,3). These rates are comparable to non–college students, with the
exception that non–college students are less likely to engage in heavy episodic
drinking. Although estimated prevalence of DSM-IV-defined alcohol abuse and
dependence varies across studies, ~18%-21% of college students meet criteria
for an alcohol use disorder (8%-13% abuse, 7%-13% dependence) (4,5). While
many students mature out of problematic alcohol use over time, an estimated
43% of students diagnosed with an alcohol use disorder during early college
continue to meet criteria (ie, are not in remission) after college (6).
Alcohol-Related Problems and Consequences

The NIAAA Task Force on College Drinking categorized college student
drinking consequences as damage to self, others, or the institution (7). A wide
variety of problems and consequences occur in relation to drinking by college
students, such as death, injury, assault, sexual assault, unsafe sex, health
problems, suicide, drunk driving, academic problems, vandalism, property
damage, and police involvement.
Damage to Self
Nausea, vomiting, and hangovers are among the most commonly reported
negative physical effects produced by alcohol (7). Structural changes to the brain
can occur until an individual is 22 years old (8). Beginning to drink before that
age places an individual at risk of having slower development of cognitive
processing skills and intellectual functioning (8). This may contribute to results
indicating that ~25% of college students report negative academic consequences
due to drinking, including missing or falling behind in class, doing poorly on
exams or papers, and receiving lower grades (9). Higher levels of drinking are
associated with poorer academic performance, as indicated by grade point
average (10). College students risk legal consequences (in addition to injury or
death) by driving under the influence (29%) (3) and/or may be involved with
local or campus police because of drinking (5%) (11). This misbehavior may be
exacerbated in individuals who begin drinking at an earlier age. Doing so can
cause neurodevelopmental delays and consequences such as an immaturity of
cognitive capacities and an inability to effectively inhibit behavioral responses
(8).
Damage to Others
In addition to direct harm to self, there are numerous secondary effects, or
damage to others, from heavy alcohol use. These include motor vehicle
accidents, vandalism, litter, noise, fighting, public urination, vomiting, and
problematic encounters with drunken individuals. For example, among students
who live on campus and drink either lightly or not at all, 60% experienced
interrupted study or sleep due to other students’ drinking, 48% took care of a
drunk student, and almost 20% had a serious argument or experienced an
unwanted sexual overture (for females) where alcohol was involved (11). It is
estimated that approximately half a million college students annually are
unintentionally injured because of drinking; 646 000 experience physical assault
by another drunken student; and 97 000 experience alcohol-related sexual assault
(2). Increased awareness of sexual assault and rape on campus has prompted
research to further investigate the impact of alcohol on campus sexual assault
(12). Findings include that sexual assaults tend to occur at colleges with high
rates of binge drinking and that three of four students who reported a sexual
assault were under the influence of alcohol during the assault (13,14).
Damage to Institution
College administrators, staff, and campus police often have to deal with the
consequences of students’ alcohol use. Resulting problems, such as violence,
vandalism, and property damage, are relatively common. More than one-fourth
of colleges with low rates of drinking, and more than half of those with high
rates of drinking, report moderate to major problems with alcohol-related
vandalism and property damage (15). Approximately 11% of students have
damaged property while under the influence (11). Further, sporadic binge
drinkers and frequent binge drinkers were four and ten times more likely,
respectively, to report having damaged property than were nonbingers (16), and
it is estimated that 50%-80% of violence occurring on campuses is alcohol
related (17).
Risk Factors for College Student Drinking

Identified risk factors for heavy drinking among college students include
demographic and environmental influences, cognitive and motivational factors
(eg, perceptions of the normative nature of drinking, expectations of positive
outcomes from drinking), and affective factors (mood or anxiety problems, a
desire to avoid negative emotions or enhance positive ones) (18). Research on
risk factors for alcohol use disorder includes a focus on the influence of parental
drinking through behavioral modeling and genetic predisposition to problematic
alcohol use. While these factors are at play across developmental stages, college
student drinking is predominantly considered a contextually limited pattern of
use characterized by high rates of alcohol use that does not typically persist past
students’ transition to postcollege roles. The tendency for college students to
moderate or “mature out of” high rates of drinking is often attributed to their
adopting a more conventional lifestyle toward the end of college (19–21).
However, a family history of alcohol use disorder makes it less likely that an
individual will experience maturation effects with respect to alcohol use (19).
Demographics
Sex and Ethnicity
On average, college men drink more often, consume larger quantities of alcohol,
and are more likely to engage in heavy episodic drinking than are college
women (3,22). College men are also more likely to meet criteria for an alcohol
use disorder and experience more alcohol-related problems (23–25). However, it
has been hypothesized that current measures of alcohol-related problems
emphasize externalizing behavior problems and neglect internalizing problems
(eg, drinking related to the management of anxiety and depression), which may
be more prevalent in females, suggesting that current estimates may be
underrepresenting negative consequences of alcohol use for women (26).
Though the majority of research continues to suggest that men drink more and
more often than do women, there is some evidence for an epidemiologic shift
toward reduced gender differences in alcohol use patterns and alcohol disorders
(27–29).
Research on both the national and local levels has found that White college
students are the most likely to engage in heavy episodic drinking. White college
students and Native American/Alaskan Native students tend to experience more
problems related to drinking (15,30). In contrast, African American students are
least likely to engage in heavy drinking and are less likely to experience alcohol-
related problems, followed by Asian American students (30). Based on a review
of national studies of adolescents and young adults, O’Malley and Johnston
estimated that 40%-50% of White students engage in heavy episodic drinking, in
comparison to 30%-40% of Hispanic/Latino and 10%-20% of African American
students (30). African American female college students drink proportionally
less than do African American male students, while the gender difference is less
pronounced among Hispanic/Latino and White students.
Athletics
For both males and females, involvement in athletics at the high school or
college level is associated with more frequent drinking, including heavy episodic
drinking and other risk behaviors (31–34). Drinking rates vary from in-season to
off-season, resulting in significantly reduced use and/or consequences during the
competitive season and increased use and/or consequences when the season ends
(35–38). Students in team sports tend to report higher drinking and binge
drinking rates than do students in individual sports (32,39,40). Expectancies,
particularly positive outcome expectancies for alcohol consumption, are
associated with heavier drinking by student athletes (41–44), despite the fact that
many of these expectancies are placebo effects rather than pharmacologic effects
of alcohol (41,42). Team captains and leaders are particularly vulnerable to these
behaviors, since the increasing level of athletic participation from
nonparticipation to team captain is positively associated with binge drinking
(31).
One need not be a team member to be at high risk for alcohol-related
problems associated with athletics—across 140 colleges, students (team and
nonteam members) who rated athletics as important to them (including fans, club
sport athletes, and intramural competitors) had higher rates of heavy drinking
(11).
Membership in the Fraternity/ Sorority (Greek) System

Fraternity and sorority organizations are environments in which heavy drinking
is considered normative and also seen as a sexuality, friendship, and socialization
enhancer (45,46). Members of the Greek system consume alcohol at greater
frequencies and quantities than do their non-Greek peers (15,47,48). Caudill et
al. (47) surveyed more than 3400 members of a single national fraternity across
32 states and found that 97% drank alcohol, 86% were heavy episodic drinkers,
and 64% were frequent heavy episodic drinkers (five or more drinks per
occasion on three or more occasions in the past 2 weeks). Greek membership has
consistently been shown to be a risk factor for heavy episodic drinking,
especially among males (15,46,47,49,50), and both selection (heavier drinking
students choose to join the Greek system) and socialization (peer influence and
drinking culture impact the drinking behavior of members after they join) have
been found to influence drinking by fraternity and sorority members (46,48,49).
However, there can be a great deal of variability in drinking rates within a
fraternity or sorority, and not all Greek organization members drink heavily or at
all (46).
VETERANS AND MILITARY SERVICE
MEMBERS
The U.S. Post-9/11 Veterans Educational Assistance Act of 2008 (the Post-9/11
GI Bill) provides over 2 million US veterans who served in either Afghanistan
(Operation Enduring Freedom, OEF) or Iraq (Operation Iraqi Freedom, OIF)
with the opportunity to attend college full time (51). Although the Post-9/11 GI
Bill gives OEF/OIF veterans access to educational benefits, many veterans will
return from deployment with physical and psychological challenges that may
impede their academic success (52). In particular, research suggests that
OEF/OIF veterans have high rates of alcohol use and psychiatric disorders that
can interfere with class attendance, decrease grades, and tests scores and lead to
withdrawal/dropout from college (53). Further, the transition from the
battlefield to the classroom can be filled with unique stressors that veterans
may not be prepared to handle. Despite the potentially negative effects of
alcohol use and psychiatric symptoms on academic success among OEF/OIF
veterans, relatively little research has actually examined this relationship. A
recent small study (N = 27) at a 4-year state university found that 73% of
veteran college students who participated reported experiencing a difficult
transition from military to college life, 62% felt academically unprepared for
college, 21.4% reported a diagnosis of posttraumatic stress disorder (PTSD),
and 14.3% reported a diagnosis of depression (54,55). Other research has
shown that veteran college students’ past year alcohol use was higher than that
of students in general (87.3% vs. 82.5%, respectively), but veteran students
engage in heavy episodic drinking at a rate similar to other students (39.1% vs.
36.8%, respectively) (56). Collectively, these data suggest that returning
veteran students are at risk for psychiatric symptoms and heavy alcohol
consumption, both of which could interfere with their academic success.
Individual and Environmental Risk Factors

Drinking Expectancies and Motives
Alcohol outcome expectancies refer to the set of beliefs one carries about the
positive and negative effects of alcohol consumption and have been shown to
predict both current and future alcohol use (57–62). Drinking expectancies begin
to form as early as the third grade (57). The anticipated valued effects of alcohol
consumption (eg, positive expectancies) are stronger predictors of drinking than
are possible negative effects (eg, negative expectancies) (58). Positive
expectancies have been shown to predict drinking (59) and to differentiate
between problem and nonproblem college student drinking (58) and are
associated with higher rates of lifetime alcohol use (57,63). Furthermore,
positive expectancies have been found to explain a large degree of variance in
the relationship between early experiences with alcohol (eg, parental, peer, and
media modeling) and subsequent problem drinking in adolescence and in college
(57,64). Expectancies measured with both explicit (eg, assessing conscious
attitudes) and implicit (eg, assessing attitudes that are out of our awareness)
measures predict alcohol consumption (65). Recent evidence indicates that
implicit measures predict additional unique variance over explicit measures of
alcohol expectancies (66). Furthermore, expectancies can be primed out of
conscious awareness. Friedman et al. (66) presented participants with either an
alcohol cue word (eg, drunk, vodka, keg) or a control cue word (eg, cup, tea, ice)
for 40 ms during what participants believed to be a lexical decision task.
Participants with higher expectancies that alcohol increased sexual desire and
who were primed with an alcohol cue word reported increased rating of sexual
attraction to pictures presented. This indicates that expectancies influence
alcohol use and can operate outside of awareness. Although expectancies are
associated with both the onset and maintenance of alcohol use, studies
evaluating interventions that challenge expectancies have demonstrated some
efficacy, but results have been mixed; therapeutic effects, when present, are not
maintained after a short period (ie, 4 weeks) of time (67).
Expectancies likely develop into motives, or a person’s stated reason for
drinking or not drinking, over time. Drinking motives are based on anticipated
positive or negative reinforcement and predict alcohol use behaviors (68–72).
The most cited drinking motives are conformity—drinking to avoid social costs
or rejection, enhancement—drinking to enhance positive mood, social—drinking
to obtain positive social rewards, and coping—drinking to regulate negative
affect (68). Of these motives, social and enhancement motives, or anticipation of
positive reinforcements (eg, drinking to induce a positive mood), are most
commonly endorsed by college students (70–72), followed by coping motives
(eg, coping with feelings of depression or anxiety) or negative reinforcement
(73,74).
Different motives are associated with differing patterns of use. In a review of
the drinking motive literature for individuals aged 10-25, Kuntsche et al. (70)
noted that social motives are more typically associated with light, infrequent,
nonproblematic use of alcohol and have been shown to be negatively related to
heavy drinking and negative consequences. Alternatively, enhancement and
coping motives are most strongly associated with heavy alcohol use, and coping
motives are further associated with more alcohol-related problems. The well-
documented relationship between coping motives (eg, drinking to cope with
depressed mood or anxiety) and problematic alcohol use is thought to represent a
type of self-medication of emotional distress (75,76). Although the lack of a
strong association between social motives and alcohol-related problems is a
reasonably robust finding, recent evidence suggests that this association may
differ by gender. LaBrie et al. (71) demonstrated that for female college students,
social drinking motives not only predicted quantity of alcohol consumption but
also were directly associated with alcohol-related consequences, calling for more
study of women’s unique reasons for alcohol use and consequences.
Beyond a direct relationship to alcohol use behaviors, drinking motives have
been found to mediate the relationship between a range of genetic,
environmental, and individual difference factors and alcohol use (77–85). LaBrie
et al. (86) examined the role of college adjustment and found that poor
adjustment mediated the relationship between coping motives and drinking
consequences, highlighting the importance of interventions to help students
decrease stress and develop good coping skills. Drinking motives also appear to
change with age and developmental stage. Littlefield et al. (87) prospectively
assessed individuals over a 16-year period, beginning at the first year of college.
They found that enhancement motives decreased from age 18 to 35, as did
alcohol-related problems.
Social Norms and Misperceptions

One of the major forms of human learning is facilitated by the process of
modeling—whereby one individual or group displays a behavior that others
imitate. One consistent finding is that college students overestimate the rates at
which other college students drink (46), the amount they consume when drinking
(88), and the extent to which other students support heavy drinking (26). The
degree to which students overestimate other students’ drinking predicts their own
increased consumption (89), an overestimation that is among the strongest
predictors of college student drinking when controlling for a variety of other
individual risk factors (90). Identification with a specific reference group (eg,
same sex, same race, same Greek status) within a larger reference group (college
students) is a moderator of the relationship between perceived group drinking
norms and own drinking levels such that the greater the identification with the
group the more similar the individual drinking levels (91).
Environmental Risk and Protective Factors

Environmental factors can also influence alcohol consumption, and college
students have been found to seek out environments that facilitate binge drinking
(92–94). Presley and colleagues noted that the cost of alcohol in and surrounding
the campus environment is related to alcohol use such that as the total cost to
drink increases, consumption decreases (22). This has significant implications
for colleges surrounded by bars frequently offering drink specials or “happy
hour” promotions in which the cost of a drink is dramatically reduced for a
limited amount of time (which hastens the rate of consumption) (22). The
authors also note that when multiple drinking venues exist, long-term and short-
term drinking problems increase. Clapp and Shillington (95) found that, among
other predictors, students who were in a setting where many people were
intoxicated were almost 13 times more likely to report consumption of five or
more drinks.
Events associated with high rates of drinking are generally well known (eg,
New Year’s eve, St. Patrick’s Day, spring break, Halloween, and high-profile
sporting events) or may be personal (eg, 21st birthdays, graduations, or
celebrating major accomplishments) (96). Consuming alcohol prior to departing
for one’s intended social activity or eventual destination is referred to as
“prepartying,” “pregaming,” “front loading,” “preloading,” or “prefunking” (97).
Increased blood alcohol concentrations and a higher incidence of consequences
are associated with prepartying, particularly for women (98). One-third of
students who violate their campus alcohol policy prepartied on the night the
violation occurred (99). For those who preparty at least once per month, the type
of alcohol consumed varies by gender (100) and, up to 50% of the time, involves
the playing of “drinking games.” Drinking games can be as simple as having
everyone drink when a word or phrase is uttered during a movie, can be time
focused (eg, one sip per minute), can be team sport focused such that losers of a
game must drink (eg, “beer pong”), or could be quite complicated with a range
of rules surrounding gambling, card games, motor skills, or verbal skills (99).
Drinking games have been identified as a risk factor for “problematic” drinking
(18) and have been associated with heavy drinking episodes (95). In some
places, there is a birthday tradition of downing one shot of hard liquor for every
year of age. This behavior increases risks for frank alcohol poisoning and/or
aspiration of vomitus.
Involvement in athletics is associated with risk for higher rates of drinking
and for consequences associated with alcohol consumption (18,101), and
drinking-game participation can be associated with risky drinking for those
involved in athletics (102,103). Yet, the culture surrounding collegiate sporting
events seems to also influence and be influenced by alcohol with many students
and alumni participating in “tailgating,” significant sporting events being
associated with increased drinking, a high frequency of alcohol advertising aired
during televised sports, and the general association of alcohol with celebration
(96,101,104).
Some environmental variables can serve as protective factors against high-
risk drinking. Many colleges have seen the emergence of designated substance-
free housing options and 12-step recovery groups on campus. Students may self-
select into various living options (eg, Greek systems, residence halls, and
substance-free housing). Research suggests that living in a designated substance-
free housing environment, even for those who drink, is a protective factor for
negative consequences (eg, heavy episodic drinking) and is associated with
increased use of preventive behaviors (eg, decreasing drinking-game
involvement and increasing use of a number of strategies for altering one’s
approach to drinking) (105). Clapp and Shillington (95) found that the only
protective variable associated with lower risk of heavy episodic drinking was
whether the event in which drinking occurred was a date. In attempting to
explain this finding, the authors speculate that students who are dating may be
less likely to use alcohol as a “social lubricant” and suggest that additional
research is needed to further examine this apparent protective factor.
PREVENTION STRATEGIES AND

INTERVENTIONS
College Drinking Prevention Strategies

Considerable research has focused on development of prevention and
intervention approaches for this population. The NIAAA’s influential 2002
report of the Task Force on College Drinking (106) represented the joint efforts
of researchers and college presidents to address the harms of and solutions to
college drinking. The Task Force report designated four tiers of prevention
strategies:
Tier I interventions have documented and replicated evidence of efficacy in
college populations. Interventions may be delivered in an individual or
group setting with a facilitator.
Tier II interventions have documented evidence of efficacy in general
populations and could be adapted for college students.
Tier III interventions show logical and theoretical promise but need more
research.
Tier IV interventions show no evidence of effectiveness.
The Task Force report was accompanied by increased college drinking

prevention research supported by the NIAAA, the Department of Education, and
the Substance Abuse and Mental Health Services Administration (SAMHSA). In
addition, several comprehensive reviews of the prevention literature have been
conducted subsequent to the Task Force report (107–115), and the report was
updated in 2007 to reflect these findings (1).
In 2015, the NIAAA created the College Alcohol Intervention Matrix
(CollegeAIM) to help college administrators review findings regarding the cost
and effectiveness of college drinking interventions and choose the optimal mix
of strategies for their campuses (116). Thus, there has been considerable
progress and a growing consensus to find what works in college drinking
prevention.
Individually Focused Interventions

Each intervention listed in Tier I (having documented empirical evidence of
efficacy) of the NIAAA Task Force report on College Drinking (106) has an
individually focused intervention component. Research supporting the efficacy
of these approaches has typically evaluated their use with students mandated to
treatment (eg, sanctioned to complete a program after a policy violation), high-
risk drinking first-year students, students within the Greek system, individuals
who screen positive for alcohol use disorders in either a health or a counseling
center setting, as well as other groups of students on campus. Additionally,
studies have examined peer versus professional delivery and the efficacy and
benefits of Web-based delivery of interventions.
Multicomponent Skills-Based Interventions

Multicomponent skills-based interventions (eg, the Alcohol Skills Training
Program—ASTP) typically combine cognitive–behavioral skills training (eg,
identifying and planning for or avoiding risky situations; using protective
behavioral strategies such as drink spacing, counting drinks, and setting limits to
reduce intoxication during drinking events; discussing myths about alcohol’s
effects; and communicating assertively about drinking decisions) with norm
clarification (eg, correcting misperceptions about drinking norms, exploring
assumptions that everybody drinks), using a motivational interviewing (MI) style
to reduce resistance and promote change (117). The CollegeAIM (116) reviewed
32 studies including a multicomponent skills intervention and found that 20 of
32 produced statistically significant reductions in alcohol use, harmful
consequences due to drinking, or both. Methodologically, stronger studies (eg,
larger samples, longer follow-up, appropriate control groups) were the most
likely to report statistically significant effects of the multicomponent skills
approach.
Expectancy Challenge Interventions

The second Tier I cognitive–behavioral intervention is expectancy challenge
interventions. Expectancy challenge interventions are aimed at changing
students’ positive expectations for alcohol intoxication and are delivered by two
methods. The first method is experiential. Participants are informed that they
will either be receiving alcohol or a placebo, and the alcohol placebo effect is
directly applied to demonstrate how one’s expectations about drinking influence
his or her experience. As part of the intervention, students are told they are
drinking alcohol but actually receive a nonalcoholic drink (eg, a placebo). These
students still show the social or interpersonal effects associated with drinking for
them (eg, they become more social, talkative). Alternatively, students are told
they are not drinking alcohol when their beverage is actually alcoholic. These
students do not exhibit the expected social effects of alcohol; instead, they feel
some of the physical effects of drinking (eg, feel sleepy, flushed) but attribute
these feelings to factors other than alcohol.
The second method is didactic, wherein students are educated about these
phenomena (eg, discussion of alcohol myths, such as “I cannot be outgoing at a
party without alcohol,” and placebo effects). Initial reviews suggested that
demonstrations of the placebo effect were associated with reduced alcohol use at
short-term follow-up for college males (108,118). Education about the placebo
effect alone did not show the same effect in reducing drinking. More recent
reviews found that 6 of 13 studies using experiential demonstrations of the
alcohol placebo effect produced short-term reductions in alcohol use (116).
Again, these results were more consistent for men than women (119). Although
one study (120) suggested that education about the placebo effect may have
harmful effects (increased drinking post-intervention) for women, two more
recent studies (121,122) found that demonstrating the placebo effect was
associated with reductions in alcohol use for both men and women.
Overall, results regarding the efficacy of expectancy challenge interventions
are encouraging but mixed and suggest that implementation of expectancy
challenges in single-gender groups may be more effective than mixed-gender
challenges, especially for women (119). Practical issues regarding the
demonstration of the placebo effect (eg, administering alcohol to college
students as part of the intervention) may limit wider application of this approach.
Brief Motivational Interventions

MI, based on the work of Miller and Rollnick (117), is a nonjudgmental,
nonconfrontational approach that emphasizes meeting people where they are
with regard to their readiness to change. For example, when people are
ambivalent about changing a behavior (eg, problematic alcohol use), MI can be
used to explore and resolve that ambivalence, and when people have not yet
considered change, MI strategies can be used to prompt thinking about change.
There is strong evidence and growing consensus that brief, in-person
motivational feedback interventions (typically incorporating assessment and
feedback regarding alcohol use, norms, and consequences) or brief motivational
interventions (BMIs) are effective in reducing and preventing excessive alcohol
use and related harm in college populations (108,109,113–115).
Listed in the Task Force report as a Tier I intervention, Brief Alcohol
Screening and Intervention for College Students (BASICS) developed by
Marlatt et al. (123,124) includes a comprehensive assessment followed by a 1-
hour personalized feedback interview. The interview is delivered in MI style,
using specific strategies such as open questions, reflective listening,
summarizing key observations or points, and supporting and affirming the
student. The approach is designed to elicit personally relevant reasons for change
(eg, change talk) and the adoption of cognitive–behavioral strategies to
implement the desired changes. The interview is structured around a review of
graphic feedback generated from the assessment (Table 43-1).
Table 43-1 Clinical Example of Brief Motivational

Intervention (BASICS)
Larimer and Cronce (108,109,114,115) reviewed 40 BMI studies of college
drinking, most involving BASICS or similar interventions, and found that 36 of
40 were associated with reductions in alcohol use, consequences, or both, across
follow-up periods up to 4 years. Alcohol-related consequences and amount or
pattern of alcohol use (rather than abstinence from alcohol) are the typical
outcomes assessed in BMI studies of college students. Recent research has also
suggested that personalized BMI content is more effective at reducing alcohol
use and related problems than nonpersonalized BMI content (which can often
vary between studies) (125–127). A meta-analysis (127) indicated that effect
sizes for these interventions were generally in the small-to-medium range, with
effects on alcohol use emerging within 1 month and effects on consequences
emerging 6 months or more after intervention. Some research, though not all,
suggests that effects weaken or decay by a 12-month follow-up.
One must note that a diagnosis of alcohol use disorder during
adolescence/young adulthood is relatively unstable relative to later in life and
that the natural trajectory of alcohol use in college and young adulthood is for a
reduction in use over time even without intervention or within the control group
(6,19,123,127). Thus, these interventions may work to hasten the natural
developmental progression out of high-risk drinking. In contrast, some research
suggests that BMI effects persist or emerge over longer follow-up periods, up to
4 years post intervention (128,129). Studies have successfully employed BMI
approaches in both group (130) and individual formats (121,131), with men
(131), women (130), mixed genders (121), and high-risk volunteers (123), as
well as mandated or judicially referred students (129,132,133). Further, this
strategy has been successfully implemented in a variety of settings, including
campus health clinics (134,135) and fraternities (131). A majority of BMI
studies focused on efficacy of this technique; however, newer studies have
looked at effectiveness (136). Thus, this type of intervention appears to be
flexible and robust, reliably producing drinking reductions in a wide segment of
the campus population in efficacy studies.
Feedback-Only Interventions
Though BASICS and related motivational interventions have substantial
evidence of efficacy and have been successfully utilized in a variety of settings,
there are barriers to the more widespread utilization of this approach.
Specifically, the approach requires the availability of trained providers and the
resources and time to meet individually or in small groups with students. Some
of these barriers can be reduced through the use of trained peers to provide the
intervention (131,137) rather than professional providers and/or the integration
of brief interventions into health or mental health settings through training of
existing providers (134).
Nonetheless, the majority of campuses do not have the resources to extend
in-person BASICS to all students who would benefit from intervention, nor do
all students who would benefit want to attend an in-person session. As a result,
researchers and practitioners have begun to evaluate more cost-effective methods
for reaching a broader audience of students, using minimal intervention
strategies such as provision of written, mailed, or Internet-based motivational
feedback. In addition, studies have evaluated the extent to which in-person
intervention improves efficacy in comparison to feedback alone. Results of this
research are encouraging.
The CollegeAIM reviewed 31 interventions involving an assessment
component and a mailed, computerized, or written motivational feedback
component (116). Twenty-six of 31 interventions were associated with
reductions in alcohol use after intervention. A mailed feedback and tips
intervention was found to both prevent initiation of drinking among abstainers
and reduce likelihood of heavy drinking among heavy episodic drinkers at a 1-
year follow-up (138).
Two studies found no differences between in-person and mailed or written
feedback, though neither study included an assessment-only control condition
(132,138). A meta-analysis by Carey et al. (127) found that effect sizes were
largest for in-person, individual motivational feedback interventions as
compared to mailed/computerized interventions. Nevertheless, they found that
feedback alone was associated with significant reductions in drinking. A meta-
analysis identified nine studies that evaluated the effects of computerized and
Web-based normative feedback in reducing drinking and drinking-related harms
(139). These interventions provide simple information comparing the
participant’s own use to his or her perceptions of the typical college student’s
drinking pattern and the actual norm for college students (140). All nine studies
found reductions in alcohol use over follow-up periods ranging from 1 to 6
months.
Some evidence suggests that gender-specific information (ie, comparison to
typical same-sex college student) improves outcomes for both men and women
as compared to gender-neutral information with larger effects for women who
identified strongly with typical college females (141). Taken together, these
findings suggest that minimal interventions involving mailed or computerized
feedback may be an important addition to the overall college drinking prevention
toolbox.
An even simpler behavioral approach has shown efficacy in several recent
studies of college drinking prevention. Specifically, Larimer and Cronce
(108,109,114,115) reviewed five studies of self-monitoring or self-assessment of
alcohol use and/or consequences in the absence of other intervention strategies.
Four of five studies reported significant reductions in alcohol use and/or
consequences. For example, Carey et al. (142) found that adding a timeline
followback interview (a method for assessing drinking in detail on a daily basis
over the past 3 months) to a standard assessment (143) resulted in reductions in
peak and typical quantity as well as frequency of heavy consumption at a 1-
month follow-up. This beneficial effect of recalling and reporting one’s drinking
levels to others may also contribute to increased self-awareness of harmful
drinking patterns and to the overall efficacy of approaches utilizing screening
and brief intervention methods (110,144).
Pharmacotherapy
There is a lack of research on the use of pharmacotherapy (disulfiram,
naltrexone, acamprosate) with college students for the treatment of alcohol use
disorder. This may in part be caused by the lack of college students who self-
refer for treatment. A large proportion of college students receiving treatment are
mandated and either may not be aware of nor interested in pharmacotherapy or
may be reluctant to use a medication that can cause them to experience
unpleasant sensations (eg, nausea) while drinking. One study examined the
effects of naltrexone on alcohol drinking, urge to drink alcohol, and alcohol-
induced sensations and mood in individuals near college age (participant age
range, 21-32 years old) (145). The double-blind, placebo-controlled study found
that individuals using naltrexone drank relatively less alcohol and drank alcohol
more slowly. There was no significant difference found in urge to drink. These
findings suggest that medication may be helpful in decreasing amount of
drinking. However, the challenge remains in motivating college students to seek
pharmacotherapy for alcohol use disorder.
Structural Interventions
With data clearly supporting the use of brief interventions with high-risk or at-
risk college students, optimism surrounds efforts to decrease harm and risk
among college students who choose to drink alcohol. An important factor in the
success of these efforts, however, is addressing the context in which alcohol use
is occurring. Therefore, efforts to intervene at the level of environment are
considered key. Recognizing the importance of context, the NIAAA Task Force
on College Drinking (106) and their CollegeAIM Matrix (116) outlined several
environmentally focused approaches.
With the amount of empirical data varying across approaches, these
environmental strategies correspondingly vary between Tier II (strategies with
demonstrated effectiveness with general populations) and Tier III (promising
approaches that need further study). The report encouraged colleges to consider
implementing these approaches as part of their overall strategic plan and to assist
in evaluating strategies with less of an established evidence base to add to the
field’s understanding of “what works.” Such approaches include (106,116) the
following:
Increased enforcement of minimum drinking age laws (Tier II). Despite

interest in lowering the drinking age (eg, the “Amethyst Initiative”
introduced in 2008), most studies have indicated that higher legal drinking
ages are associated with reduced alcohol consumption, and over half
demonstrate that higher legal drinking ages are associated with decreased
rates of traffic crashes (106,116). Despite conventional wisdom that lower
drinking ages in European countries are associated with more moderate
consumption patterns and reduced harm, cross-cultural research with
college students indicates that young adult college students in countries
with lower drinking ages actually drink more and have more alcohol-related
consequences than US students (146).
Increased publicity about and enforcement of underage drinking laws on
campus and eliminating “mixed messages” (Tier III) (106,116).
Restrictions on alcohol retail outlet density (Tier II). Research shows that
higher outlet density, particularly around college campuses, is associated
with increased binge drinking (106,116).
Consistently enforcing disciplinary actions associated with policy violations
(Tier III). The NIAAA noted that failure to do so may suggest that “rules
were made to be broken (p. 22)” (106).
Informing new students and their parents about alcohol policies and
penalties before arrival and during orientation periods (106).
The list above represents only a sample of the various approaches listed by the
NIAAA, and it is important to emphasize that any one strategy implemented on a
college campus must be part of an overall strategic plan that may need multiple
components to enhance success.
DeJong and Langford (147) recommend a college-focused prevention
typology that identifies environmental change as one of the four areas of
intervention. They outline five subcategories of strategic interventions within
their environmental change category:
i. Promoting alcohol-free options (eg, creating or promoting alcohol-free
events, publicizing volunteer opportunities, expanding hours for
alcohol-free settings, promoting consumption of nonalcoholic
beverages at events)
ii. Creating an environment that supports health-promoting norms (eg,
modifying the academic schedule, offering substance-free residence
halls, increasing faculty–student contact, creating programs to correct
student misperceptions of drinking norms)
iii. Limiting alcohol availability on- and off-campus (eg, banning or
restricting use of alcohol on campus, instituting responsible server
training programs, limiting number and concentration of alcohol
outlets near campus)
iv. Restricting alcohol promotion and marketing on- and off-campus (eg,
banning or restricting alcohol advertising on campus, banning alcohol
promotions with special appeal to underage drinkers, instituting
cooperative agreements to limit special drink promotions)
v. Developing and enforcing policies and laws surrounding alcohol
consumption (eg, revising campus policy as needed, increasing
checks of identification at on-campus functions, increasing
disciplinary sanctions for violation of campus policies)
In a discussion of specific high-risk events associated with problematic college
drinking, Neighbors et al. (96) provide a number of recommendations involving
environmental-level interventions for spring break, a notably high-risk situation
with both heightened frequency of consumption and negative consequences (eg,
sexual assault, legal involvement, lethal intoxication). Recommendations include
inviting parents to visit campus during spring break, providing alternative
activities (eg, community service trips), advertising lower-risk activities early
before students plan spring break trips, and encouraging faculty to schedule
major papers or exams the week after spring break. Similarly, when considering
prevention of risky drinking games, another activity associated with increased
alcohol consumption and negative consequences, Borsari (148) noted the
importance of providing social alternatives to drinking games and taking steps to
ensure students are aware of nondrinking-related activities as part of an
environmental strategy.
Steps can be taken to promote an environment that may increase the
effectiveness of minimum drinking age laws (149). Keeling (150) found that
laws restricting underage drinking and governing the volume of sales are
associated with lower levels of drinking. Because inconsistent and ineffective
enforcement of drinking laws is often a problem, Kypri et al. (151) stress the
importance of effective communication surrounding laws, including clear
definitions of key terms in increasing the impact of alcohol-focused regulations.
For example, there is no clear definition of intoxication. It may refer to visible
signs of inebriation or that an individual has consumed alcohol and it is affecting
behavior (even if it is not obvious). More clarity could aid in enforcement.
As recognized by the NIAAA Task Force (106), community-based
interventions have demonstrated efficacy in reducing alcohol use and related
consequences (2,152,153). Although only a subset of these interventions have
been specifically developed for use with younger drinkers, all programs included
major targets related to alcohol use in teenagers and young adults and are
relevant to college drinking issues. Programs have differed widely on key factors
(eg, selection and makeup of targeted communities, intervention strategies,
outcomes assessed), and at this point in time, little is known about comparative
efficacy. These factors aside, community-based interventions demonstrated
significant reduction in alcohol sales to minors, alcohol consumption, self-
reported drinking and driving, automotive crashes involving alcohol, and
alcohol-related fatal crashes (153). When the community and college or
university campus both stand to benefit from efforts aiming to reduce
consumption or related consequences, use of a campus–community coalition has
been encouraged (147).
A campus–community coalition typically assembles key stakeholders from
both settings who can collaborate in efforts to reduce problems on campus and in
the surrounding area. Stakeholders generally include faculty, student leaders,
administrators, staff (residence life, counseling center, health center, etc.), police,
bar or restaurant owners, or landlords near campus. Clapp and Stanger (154)
detail four examples in which a coalition (eg, the Collegiate-Community
Alcohol Prevention Partnership) successfully worked with bars frequented by
students to provide responsible beverage service training and to take steps
toward modifying advertising practices, took steps to halt a bus provided by a
bar in a Mexican border town that was unsafely transporting students, provided
students with tips on hosting a safe party, and worked to remove paraphernalia
associated with the promotion of heavy drinking from campus stores.
Since the original NIAAA Task Force report (106), community-based
interventions such as these have been applied specifically to college campuses
(149). As research efforts have begun to generate a small body of literature,
studies have increasingly used more rigorous designs (eg, control/comparison
campus). Similar to community-based programs, college community programs
differ in intervention strategies and other key variables (155). As outlined by
Saltz (155), results of studies are promising with interventions providing
reductions in target alcohol-related behaviors. However, it is not known what
combination of strategies will have the greatest impact, what is the most efficient
manner to implement the strategies, and what is needed for universities to adopt
these strategies.

DIRECTIONS
Alcohol use on college campuses is an important health, safety, liability, and risk
management issue. Advances have been made in identifying effective strategies
to reduce alcohol consumption and associated consequences. Increasingly,
colleges and universities are recognizing the need for a strategic plan with
multiple components, targets, and delivery strategies as they seek to reduce the
harm associated with college student drinking.
It is important to recognize that alcohol use does not occur in a vacuum, and
attention should be paid to the context of college student alcohol use. In addition
to reported alcohol use, 41% of college students also report the use of an illicit
drug in the past year, 38% of students report past-year use of marijuana, and
19% of students report past-year use of any illicit drug other than marijuana (3).
In addition, a recent trend is for individuals to combine alcohol use with
increasingly available and popular over-the-counter caffeinated energy drinks.
This combination is uniquely problematic as the stimulant properties of these
drinks have the ability to mask the depressant effects of alcohol, leading to the
subjective impression that a person is less impaired (156). The resulting lack of
objective awareness may interfere with judgment regarding continued alcohol
intake or engagement in activities where high levels of intoxication are
increasingly dangerous. Efforts to prevent or intervene in unhealthy alcohol use
in college students will need to consider these related behaviors. Future research
efforts will need to more consistently measure the impact on other drug use
when alcohol is the focus of prevention or intervention efforts and identify
effective strategies for working with polysubstance-using college students.
Also related to the context of student alcohol use are co-occurring mental
health problems. In a national survey of counseling center directors conducted in
2014, 94% of directors felt that psychological problems were becoming more
severe (157). Schwartz (158) documented a more than fivefold increase in
students prescribed a psychotropic medication on college campuses between
1992 and 2002. A number of explanations have been suggested for the perceived
increase in the severity of mental health disorders on college campuses,
including increased management of depression, anxiety, and behavioral/learning
issues with psychotropic medications (allowing attendance of more severely ill
students that otherwise would not have attended college), students using alcohol
and drugs while on medication (resulting in an accentuation of depressant
effects), or students stopping use of medication when entering college because,
among other possible reasons, they want to use alcohol or other drugs instead
(159). Given success with brief interventions focused on depression (160) and
alcohol (109), future research must consider strategies to address the overlap of
mental health issues and substance use.
Research to date indicates that BMIs utilizing assessment and individualized,
in-person feedback are consistently efficacious in reducing alcohol use across a
number of college student settings and effectiveness trials on college campuses
have supported these findings. In addition, cognitive–behavioral skills-based
interventions have clear evidence of efficacy. Given the difficulties with
engaging students in in-person interventions on college campuses, integration of
these resources into existing points of contact (including academic courses,
residence halls, Greek social organizations, student services, and campus health
and mental health settings) holds promise for reaching students in need of
services.
Although it may seem intuitive to screen for alcohol problems in a campus
health setting, the data suggest that this is not a widespread practice. Although
approximately one-third of health centers at 4-year colleges or universities
routinely screen for alcohol problems, only 17% of these used standardized
instruments as part of their screening (161). Thus, in addition to integrating
services into points of contact, reliable and valid screening strategies should be
used (162).
There is also reason for promise as various delivery strategies are
considered. Given the success of mailed and computerized feedback
(140,156,163), the widespread implementation of online screening and brief
feedback interventions is now feasible on college campuses. Several
commercially available computerized screening and intervention products have
emerged, and many are reviewed in the NIAAA CollegeAIM (116) resources.
Although there are documented barriers to dissemination, adoption,
implementation, and maintenance of empirically tested approaches, fortunately,
these barriers are clearly surmountable (164). College student alcohol use and
associated consequences are not unique problems on any one campus. Rather,
there are shared challenges across campuses and increasingly shared successes.
As colleges and universities move toward developing campus–community
coalitions and involvement in cooperative statewide coalitions, efforts to impact
college student health move beyond the responsibility of the individual campus,
allowing for shared knowledge and resources. With ever-changing and ever-
growing student populations and venues for higher education, the challenge is
not only to meet current needs but also to adapt to needs as they shift with
demographic changes as well as structural ones.
ACKNOWLEDGMENTS
Portions of this chapter were written with grant support from the National
Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, F31
AA025531 awarded to Frank J. Schwebel, R01 AA012547 and T32 AA07455-
29, awarded to Mary E. Larimer, and from the Alcoholic Beverage Medical
Research Foundation (ABMRF)/The Foundation for Alcohol Research awarded
to Ty W. Lostutter and with fellowship support from the Group Health
Foundation awarded to Ursula Whiteside.
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CHAPTER 44
Understanding “Behavioral Addiction”
Yvonne H. C. Yau, Sarah W. Yip, and Marc N. Potenza
CHAPTER OUTLINE
Introduction
Impulse Control Disorders or “Behavioral Addiction”?
Pathological Gambling Or Gambling Disorder (see also Chapter 45)
Binge Eating Disorder
Compulsive Sexual Behavior
Problematic Internet Use
Problematic Video-Game Playing/Internet Gaming Disorder
Compulsive Buying Disorder
Conclusion
INTRODUCTION
The term “addiction” is derived from the Latin word addicere, meaning “bound
to” or “enslaved by” (1). In its original formulation, the word was not linked to
substance use behaviors. As of several hundred years ago, the word became
associated first with excessive alcohol and then with excessive drug use (2). By
the time of the 1980s, the word was almost exclusively linked to excessive
patterns of substance use, with experts involved in generating diagnostic criteria
for drug dependence (as defined in editions of the Diagnostic and Statistical
Manual (DSM) prior to the fifth edition, DSM-5) showing good agreement that
the term applied to the condition of compulsive drug taking (3–5). However, by
the early part of the 2000s, a growing movement to consider nondrug behaviors,
such as gambling, sex, and eating (although by strict definition, this last category
does involve a substance—food) as addictive in nature, was emerging (6). Aided
by data from neurobiological studies, this view has gained momentum, leading
to the consideration of a renaming of the “Substance-Related Disorders”
diagnostic category to “Substance Use and Addictive Disorders” in the DSM-5
(1,7–11). Currently, only pathological gambling (PG) was proposed for inclusion
in this category by the American Psychiatric Association (7), and gambling
disorder (GD, as the entity is currently named in the DSM-5 in order to reduce
stigma) is classified together with substance use disorders (SUDs) in the DSM-5
(12). Other nondrug behaviors including Internet gaming disorder (IGD), a
possible form of problematic Internet use (PIU) and compulsive sexual behavior
(CSB) (or hypersexual disorder—HD, also at times termed sex addiction), were
considered for the DSM-5, with IGD included in Section III of the DSM-5 (in
which conditions that require further research are included) and HD was omitted
(12).
Addictive disorders have been proposed to have several defining
components: (a) continued engagement in a behavior despite adverse
consequences, (b) diminished self-control over engagement in the behavior, (c)
compulsive engagement in the behavior, and (d) an appetitive urge or craving
state prior to the engagement in the behavior (1,13,14). If these elements are
considered the core features of addiction, then excessive patterns of gambling
and engagement in other non–substance-related motivated behaviors might be
considered addictions. Consistently, the term “behavioral addiction” has been
used to describe these disorders. Particularly relevant to addiction are aspects of
motivation, reward processing, and decision-making (15–17), and these features
represent potential endophenotypes, or underlying constructs that may be more
closely linked to biological processes than are diagnoses, per se, that could be
pursued in biological investigations across a spectrum of substance- and non–
substance-related addictive disorders.
Many disorders under the “behavioral addiction” umbrella terminology have
been previously considered as impulse control disorders (ICDs). The goals of
this chapter are to review similarities between behavioral addiction and SUDs
and discuss the implications for treatment and theory. First, the category of ICDs
in the DSM-IV-TR is reviewed with a focus on disorders being considered
subsequently as behavioral addiction. Evidence from neurobiological research,
clinical reports, and pharmacotherapy studies regarding these disorders and their
relationships with SUDs is reviewed. In reviewing the individual disorders,
consideration is given to disorders for which there have been arguably the most
data supporting similarities with SUDs (eg, in the areas of gambling, eating, sex,
Internet use, gaming and shopping or buying). How these disorders are currently
being considered in the eleventh edition of the International Classification of
Diseases (ICD-11) will also be discussed.
IMPULSE CONTROL DISORDERS OR

“BEHAVIORAL ADDICTION”?
Several disorders that might be considered a behavioral addiction were
categorized in the fourth edition of the DSM as “Impulse Control Disorders Not
Elsewhere Classified” (18). This title indicates that other disorders characterized
by impaired impulse control, such as SUDs, attention deficit hyperactivity
disorder (ADHD), bipolar disorder, cluster B personality disorders (ie, antisocial,
borderline, histrionic, narcissistic), among others, were categorized elsewhere in
the manual. The ICDs within the “not elsewhere categorized” section included
intermittent explosive disorder (IED), kleptomania, PG, pyromania,
trichotillomania, and ICD not otherwise specified (NOS). Additional ICDs that
were under consideration for DSM-5 included ones related to excessive Internet
use, video-game playing, buying or shopping, sex, and skin-picking or nail-
biting (19). In addition, research criteria for binge eating disorder (BED) were in
Section III of DSM-IV (20) and are now in the main section of DSM-5 (12), and
a case for inclusion of obesity was forwarded (8), albeit debated (21,22) and
rejected. As discussed above, among issues that were considered within research
workgroups were whether the ICDs might be best categorized separately, with
SUDs as addictions, or with obsessive–compulsive disorder (OCD) as
obsessive–compulsive spectrum disorders (OCSDs) (8,10,19,23,24). Although
the conceptualizations of ICDs as addictions or OCSDs are not mutually
exclusive and data exist to support each formulation, these frameworks have
important clinical implications with respect to prevention and treatment
strategies (23–26). In the following sections, we review behavioral addiction,
their main clinical features, and what is currently known regarding their
biologies. A particular emphasis is placed on GD as it is arguably the best
studied of the behavioral addiction to date and the only one classified as such in
the DSM-5. However, for a more detailed description of the clinical features of
GD and its treatment, we direct you to the chapter entitled, Gambling Disorder:
Clinical Characteristics and Treatment (27).
PATHOLOGICAL GAMBLING OR
GAMBLING DISORDER (SEE ALSO
CHAPTER 45)
GD has been considered a chronic, lifelong condition, although more recent data
are challenging this notion (1,28,29). GD and SUDs share clinical characteristics
and diagnostic criteria. Individuals with PG often experience withdrawal,
craving, tolerance, and failed attempts to reduce or abate gambling behaviors—
all common features of SUDs. The DSM-5 diagnostic criteria for GD reflect
these similarities. A diagnosis of GD requires that the patient display four or
more of the following: preoccupation with gambling; gambling with greater
amounts of money to receive the same level of desired experience (tolerance);
repeated, unsuccessful attempts to reduce or quit gambling; is restless/irritable
when trying to stop gambling (withdrawal); gambles to escape from a dysphoric
state; gambles to regain gambling-related losses (“chases” losses); lies in
significant relationships about gambling; has risked/lost a job or significant other
due to gambling; and relies on others to fund gambling. Additionally, an
exclusionary criterion exists to specify that the gambling is not better accounted
for by manic episodes.
A Nonsubstance Addiction?
SUDs and GD share phenomenological features. As with SUDs, GD often
begins in adolescence and young adulthood, and prevalence estimates of GD
tend to decrease across the life span (27). A common feature of SUDs and GD is
“telescoping”—the phenomenon whereby the time between initiation and
problematic engagement in the addictive behavior is shorter in females than in
males (30,31). These commonalities suggest that there may be shared
developmental vulnerabilities for both disorders. In particular, the high
prevalence estimates in adolescents (32) suggest common vulnerability factors
(eg, impaired impulse control) for both SUDs and GD. There additionally exist
high comorbidity rates for GD and SUDs, with co-occurrence estimates as high
as 39.0% for comorbid substance abuse in clinical populations (33) and elevated
odds observed in community samples (34–38).
Neurocognition
Neurocognitive measures provide insight into neurobiological functioning
(39–41). For example, neurocognitive research suggests a dysregulation of the
ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC) in
individuals with GD (42,43). Individuals with GD display impaired performance
on the Iowa gambling task (IGT), a task involving risk/reward decision-making
(44,45). Other populations with impaired performance on the IGT include
individuals with SUDs, schizophrenia, or vmPFC lesions. Goudriaan et al. (46)
reported that individuals with GD and individuals with a history of alcohol
dependence both had impaired performance on neurocognitive tasks involving
inhibition, time estimation, cognitive estimation, and planning tasks in
comparison to normal controls and to individuals with Tourette syndrome, who
only had an impaired performance on inhibition tasks. Neurocognitive measures
of disinhibition and decision-making are also positively associated with
problem-gambling severity (47) and may predict the relapse of GD (48). Both
individuals with problem gambling and those with alcohol dependence display
alterations in risky decision-making and reflection impulsivity—processes
involving the vmPFC—in comparison to matched controls (49). These data
highlight some of the clinical similarities between GD and SUDs and suggest
similarities in underlying neurobiological deficits (50). As such, neurocognitive
research may be a useful tool in the identification of brain regions of interest
warranting further investigation via more direct imaging-based modalities.
Delay Discounting
Individuals with GD often make disadvantageous decisions (eg, “I’ll go
gambling one last time”), selecting small immediate rewards over larger delayed
rewards (eg, preferring $20 now as compared with $40 in a month). The rapid
temporal discounting of rewards has been termed delay discounting, as rewards
are more steeply discounted as a function of delay duration (51). More rapid
discounting has been observed in multiple populations, including individuals
with SUDs (52). A dose-dependent relationship has been found between level of
alcohol use and patterns of delay discounting (52). A similar additive effect has
also been reported among heroin users in relation to needle sharing: users who
engaged in needle sharing scored more highly than did non–needle-sharing
heroin users on delay-discounting measures (52). Together, these data suggest
that multiple risk factors may contribute to rates of delay discounting.
Individuals with comorbid SUDs and GD discount rewards more rapidly than do
GD individuals without SUDs (51,53). It is unclear whether comorbid SUDs and
GD promote delay discounting or whether delay discounting is a vulnerability
factor for comorbidity.
Although some data exist to suggest that individuals with SUDs who are
abstinent display less delay discounting than do those who are not abstinent,
other data suggest no significant differences (52). A study suggests that delayed
discounting did not differ between GD individuals before treatment and 1 year
after treatment (54). To our knowledge, this is the first study that investigates
delayed discounting among abstinent GD individuals. Further research into the
effect of abstinence on delay discounting is needed.
Delay discounting involves aspects of reward evaluation, and multiple brain
regions contribute to reward processing in humans (55,56). One implicated brain
region in subjective reward valuation is the nucleus accumbens (NAcc), situated
in the ventral striatum (57–59). In healthy controls, the anticipation of working
for or receiving monetary rewards is associated with ventral striatal activation,
whereas an increase in vmPFC activation is associated with the processing of
actual reward outcomes during performance of a monetary incentive delay task
(60,61). An effective functional balance between these reciprocally connected
neural regions may mediate appropriate and advantageous behavioral responses
to varying reward contingencies. A functional magnetic resonance imaging
(fMRI) study reported increased delay discounting among pathological gamblers
as well as an association between decreased activations in the ventral striatum
and OFC and probability discounting compared to matched controls (56).
Preclinical research suggests that diminished serotonin (5-HT) activity in the
forebrain may hypersensitize animals to delays, influencing patterns of delay
discounting (62). Further research is needed to determine the relationship among
5-HT regulation, prefrontal cortical activation, and delay-discounting behavior in
humans.
Neurocircuitry
Corticostriatal and forebrain neuromodulatory systems have been implicated in
delayed and probabilistic reward (ie, delay discounting) (62). Dysregulation of
the mesocorticolimbic dopamine (MCL DA) system has been hypothesized to
contribute to GD and SUDs (63,64), although more recent data suggest that DA
may not contribute a central role as previously hypothesized (65,66). Given the
phenomenological (eg, craving, tolerance) and neurocognitive (eg, delay
discounting) similarities between GD and SUDs, it is possible that these
disorders may share similar neurobiological abnormalities, and current
investigations examining this hypothesis have identified both similarities and
differences (67–69).
There have been several fMRI studies that suggest that specific brain regions
contribute to the pathophysiology of GD. For example, Potenza et al. (70) have
reported reduced frontal cortical, basal ganglia, and thalamic activations in
response to gambling videos—during the period prior to the subjective onset of
emotional or motivational response—among GD subjects (vs. controls). This
finding differed from those observed in similar studies involving subjects with
OCD in which relatively increased activation of these regions was observed in
the patient group. In particular, when viewing the portion of the videotapes
during which the most robust gambling stimuli (eg, video clips of a gambling
public service announcement involving slot machines or an advertisement for a
casino in which table gambling is shown) were presented, individuals with PG
displayed relatively less activation of the vmPFC. Diminished activations of the
vmPFC among individuals with PG as compared to control subjects have also
been observed in other studies across a range of fMRI tasks, for example, the
Stroop color–word interference task (71), a monetary incentive delay task (72),
and a simulated gambling task (63). Similarly, individuals with SUDs either with
or without co-occurring GD show relatively diminished activation of the vmPFC
during performance of the IGT (73), in comparison to control subjects. Together,
these data indicate an important role for the vmPFC in GD.
Multiple studies also implicate the striatum in GD. For example, Reuter et al.
(63) observed significantly less vmPFC and ventral striatal activation in GD
participants compared to control subjects during a simulated gambling task. Both
right ventral striatal activation and vmPFC activation were inversely correlated
with severity of gambling symptomatology in GD subjects, indicating that the
less the activation of these brain regions, the greater the gambling pathology.
Other fMRI studies during gambling-cue exposure have similarly observed
diminished activation in the ventral (42) and dorsal striatum (74) in PG
participants (vs. controls).
Neurostructure
In recent years, multiple studies have investigated the neurostructural correlates
of psychiatric disorders using either diffusion tensor imaging (DTI) or voxel-
based morphometry (VBM) to assess white and gray matter structures,
respectively. Findings from DTI studies indicate similar alterations in white
matter microstructures encompassing regions of callosal, association, and
projection fiber tracts between GD (75,76) and SUDs (77–80). Among
individuals with GD, a history of previous DSM-IV-defined alcohol abuse or
dependence is associated with a greater magnitude of white matter
microstructural alterations within regions of the corpus callosum, and white
matter integrity within the corpus genu is associated with increased levels of
self-reported impulsivity (76). More recently in a larger sample, similar white-
matter-related alterations were observed in secondary crossing fibers in
individuals with GD and cocaine use disorder (81). Together, these data provide
evidence for white-matter involvement in the pathophysiology of GD.
Several VBM studies have been conducted among individuals with GD
(82,83). In contrast to a region of interest study finding smaller hippocampal and
amygdalar volumes in GD (84), no significant differences were reported in gray
matter volumes between individuals with and without GD in the VBM studies.
In comparison to individuals with DSM-IV-defined alcohol or cocaine
dependence, those with GD show relatively greater gray matter volumes
including within prefrontal cortex (PFC), with measures similar to those in
healthy populations (82,83). These data therefore suggests differences in gray
matter macrostructures in GD as compared with SUDs and raise the possibility
that some of the volumetric differences in SUDs may be specific to these
disorders, perhaps via substance-related neurotoxicities.
Neurochemistry
Serotonin (5-HT)
Serotonin neurons project from the raphe nucleus of the brain stem to multiple
brain regions including the hippocampus, amygdala, and PFC. It has been
hypothesized that dysregulated 5-HT functioning may mediate behavioral
inhibition and impulsivity in GD (43,85,86). Data from studies of cerebrospinal
fluid (CSF), pharmacological challenge studies, and preclinical investigations
together suggest a role for 5-HT in GD.
Low CSF levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-
HIAA) have been reported in individuals with GD (87). Low CSF levels of 5-
HIAA in humans have been associated with violence, suicidality, and impulsive
aggression (62) and observed in other psychiatric disorders including ICDs and
alcohol use disorder. Evidence from preclinical research has also identified a
correlation between risk-taking behaviors and lowered CSF levels of 5-HIAA in
monkeys (62) and rats (88). Low levels of platelet monoamine oxidase (MAO)
activity, considered a peripheral marker of 5-HT activity, have been reported
among males with GD (89,90). Consistent with findings of 5-HIAA CSF levels,
lowered levels of platelet MAO have additionally been reported in both suicidal
and risk-taking individuals (91).
5-HT receptor sensitivity has been investigated via the administration of the
5-HT1/5-HT2 receptor partial agonist meta-chlorophenylpiperazine (m-CPP).
Individuals with GD, like those with SUDs, report a euphoric or “high” response
to the m-CPP, whereas control subjects report an unpleasant response (92), along
with an enhanced prolactin response (93). In GD, this differential response was
associated with severity of GD symptomatology, with higher scores on the Yale-
Brown Obsessive–Compulsive Scale Modified for PG, a GD severity rating
scale, significantly correlating with increased prolactin responses. In response to
the 5-HT1B/1D receptor agonist sumatriptan, a blunted growth hormone and
prolactin response was observed among GD individuals (vs. controls), a
response that suggests decreased 5-HT receptor sensitivity (94), similar to that
observed among alcohol-dependent individuals (95). Furthermore, disturbances
in 5-HT function, as reflected by blunted prolactin response to m-CPP, appear
associated with severity of drug use among cocaine-dependent individuals (96).
Taken together, these studies suggest that responses to 5-HT agonist
administration are similar to those reported for substance-related addiction.
Other pharmacological studies support the hypothesis that there is a
dysregulation of the 5-HT system in GD. Among individuals with GD, 5-HT1B
receptor availability within both the ventral striatum/pallidum and the anterior
cingulate cortex (ACC) is positively correlated with problem-gambling severity
(as assessed using the South Oaks Gambling Screen) (97). In some studies,
selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine and
paroxetine, have been found to improve social functioning and reduce gambling
behaviors and thoughts about gambling in GD (98). However, clinical trial
findings involving SSRIs have generally been negative or mixed, perhaps in part
related to the high placebo response (98–102). As such, the precise role for
SSRIs in the treatment of GD remains an active area of investigation (86,103).
Dopamine
Dopamine (DA) has been implicated in rewarding and reinforcing processes in
drug addiction. There have been several ligand-based studies investigating DA
functioning among individuals with GD versus healthy controls. Linnet et al.
(104) reported in a very small sample a positive association between self-
reported excitement levels during IGT performance and DA release within the
ventral striatum among individuals with GD. Joutsa et al. (105) reported that
whereas individuals with GD and healthy controls showed similar levels of DA
release during slot-machine-task performance, DA release was positively
correlated with problem-gambling severity among GD individuals. Similarly,
there have been two reports of no alterations in overall DA receptor binding
within the striatum among individuals with GD (106,107), despite significant
correlations between D3 receptor binding and both problem-gambling severity
and impulsivity within the dorsal striatum (106), as well as between mood-
related impulsivity and D2/D3 receptor binding within the striatum (107) among
individuals with GD. Taken together, these preliminary data suggest that the
clinical presentation of GD may be partially mediated by DA (eg, DA release is
associated with gambling-related excitement and PG severity) but do not support
the hypothesis of a general alteration in DA receptor availability among
individuals with GD (65).
Psychopharmacological data suggest that the DA system may influence
impulsive behavior, although the precise manner is not completely understood.
Stimulants such as amphetamine increase DA release and prevent DA uptake
within the synaptic cleft and lead to improved impulse control in individuals
with ADHD (62). However, amphetamine administration in GD has been
associated with the priming of gambling motivations (108,109). Whereas DA
agonists have been associated with GD and ICDs in the treatment of Parkinson
disease (PD) (110–112), the DA D2-like receptor antagonist haloperidol has been
reported to enhance the rewarding and priming effects of gambling in GD (108),
though individual differences may be important (113). Investigations of CSF DA
levels in GD have also yielded equivocal findings. Decreased CSF levels of DA
and increased levels of the DA metabolites homovanillic acid (HVA) and 3,4-
dihydroxyphenylacetic acid have been reported in GD (114). However, these
findings were no longer present when correcting for CSF flow rate (87). A more
recent investigation reported increased levels of CSF HVA among individuals
with GD (115). The authors additionally reported enhanced levels of 5-HIAA, a
finding different from their earlier investigations of CSF 5-HT metabolite
concentration levels (87). These data highlight the need for studies using larger
carefully controlled samples, while accounting for potentially confounding
factors such as comorbid pathologies and CSF flow rate.
Norepinephrine and Arousal in GD

Dysregulation of norepinephrine (NE)—a neurotransmitter implicated in arousal,
attention, and sensation-seeking behaviors—has been reported in individuals
with GD. Individuals with GD have elevated urinary concentrations of NE, as
well as elevated CSF levels of a metabolite of NE (metabolite 4-hydroxy-3-
methoxyphenyl glycol) (116). Research supports dysregulated hypothalamic–
pituitary–adrenal axis regulation in GD. Meyer et al. (117) measured the
neuroendocrine responses to “real-life” casino gambling in problem gamblers
and found that problem gamblers had higher heart rates and elevated NE and DA
levels in comparison to controls. In a separate study, GD individuals (vs.
controls) showed a higher growth hormone peak response to clonidine—an
adrenergic agonist used to assess NE function—the magnitude of which was
positively correlated with problem-gambling severity (118). Together, these data
suggest that there may be an elevation of NE activity in GD that may be
potentiated by gambling behaviors.
Opioids
Pharmacological challenge studies suggest a dysregulation of the opioid system
in GD. Naltrexone and nalmefene, both opioid receptor antagonists, have been
found to reduce gambling-related thoughts and behaviors in individuals with GD
(119–122), albeit not consistently (123). Kim et al. (117) conducted a double-
blind study of naltrexone in a sample of 89 individuals with GD and found that
naltrexone (vs. placebo) administration at a mean dosage of 188 mg/d reduced
subjective craving reports. Consistent with previous research demonstrating
naltrexone’s dose-dependent hepatotoxicity, ~20% of participants displayed liver
function test abnormalities subsequent to naltrexone treatment (119,120). A
randomized double-blind study of nalmefene, an opioid antagonist that has not
been associated with hepatotoxicity, found significant improvement in GD
symptoms subsequent to lose-dose (25 mg/d) treatment in comparison to
controls (120); moreover, post hoc studies suggests that medication dosage
appears to be important in achieving symptom control (122) and that individual
characteristics (eg, family history of alcoholism or strong cravings at treatment
onset) appear associated with better responses (124). Together, these data
suggest an important role for opioid antagonists in the treatment of GD as there
is in alcohol and opioid use disorders. However, allelic variation does not appear
to influence response to opioid antagonists in GD as they do in alcohol use
disorders (125). Additional support for the involvement of opioid systems in GD
come from neurochemical studies (126).
Population Genetics
Family- and twin-based studies of addiction indicate that genetic factors are
important in the development of drug- and alcohol use disorders. Family studies
of GD suggest a significant parental influence on the development of offspring
gambling behaviors (127). Gene/environment data suggest that the cross-
generation transmission of drug addiction involves both environmental and
genetic factors. Data derived from the Vietnam Twin Era Registry found that
between 35% and 54% of the probability of meeting criteria for a DSM-III-R
diagnosis of GD were attributable to heritable factors (128). Data from the same
sample reported that 34% of the probability of developing DSM-IV-defined drug
dependence was attributable to inherited factors, suggesting similar degrees of
heritability for GD and SUDs (129). In an independent sample, 49% of the
probability of developing GD was attributed to genetic influences (130). Another
study using the same population found that GD and alcohol dependence shared
genetic and environmental contributions (131), a finding since replicated in an
independent sample (132). Shared genetic contributions have also been found
between GD and other SUDs including those relating to cannabis, tobacco, and
stimulants (133), consistent with findings from another sample (134). Shared
genetic and environmental factors may not be limited to SUDs, with both
contributing to externalizing conditions like conduct and antisocial personality
disorders as well as internalizing conditions like anxiety disorders, although
genetic factors may contribute more prominently to the co-occurrence of GD and
some internalizing disorders (130,135).
Genetic Polymorphisms in GD
Preliminary molecular genetic research suggested that specific genetic alleles
were associated with GD. Genetic polymorphisms related to genes encoding for
the DA-related moieties (DRD1Ddel, DRD2 Taq I A, DRD4 [exon III]) were
hypothesized to contribute to GD with mixed results observed (136–140).
Variants of the serotonin transporter gene promoter region (5HTTLPR) (91) and
MAOA enzymes (MAO-A [intron I], MAO-A [promoter], MAO-B [intron II])
(89,90) have been reported in association with PG. Similarities with respect to
allelic distributions have been reported in GD and DSM-IV-defined drug and
alcohol dependence; for example, variations in DRD2 and MAOA genes have
been linked to GD and alcohol use disorders, and DRD4 variants have been
linked to GD and alcohol-, cocaine-, and heroin use disorders (141). These and
other molecular genetic studies of PG should be considered preliminary in nature
given relatively small samples, incomplete subject characterization, and frequent
absence of stratification by race/ethnicity (142,143), particularly as some early
results have not replicated in studies using alternate designs (eg, discordant
sibling pairs) (137). Two genome-wide association studies failed to identify
regions of the genome reaching genome-wide significance, although the samples
were relatively small (144,145).
Conclusion
Although PG was initially included in the DSM in 1980, the precise
neurobiology of the disorder remains incompletely understood. However,
growing evidence from neurocognitive, neurochemical, neuroimaging, and
genetic research suggest that GD may share similar pathophysiologies with
disorders involving poor impulse control, such as SUDs, as well as having
unique characteristics. There are important treatment implications inherent in the
similarities and differences that may guide treatment development.
BINGE EATING DISORDER

Although specific addictive drugs have different influences on eating behaviors
(eg, weight loss with amphetamine and increased food intake with marijuana),
data suggest that both substance use and eating behaviors may be modulated by
similar motivational neurocircuitry leading to the conceptualization of “foods as
drugs” (146). This has led to the consideration of “food addiction,” albeit with
debate (22,147). The DSM-IV-TR category of eating disorders included anorexia
nervosa (AN), bulimia nervosa (BN), and eating disorder NOS, with BED being
added in the DSM-5. BED is distinct from BN as it does not include
compensatory behaviors such as purging. BED is associated with obesity and
other negative sequelae. The rise in the prevalence of obesity within the
population has led to more research on obesity and related disorders like BED.
Given that BED has an important element of episodic behavioral dyscontrol
similar to the formal ICDs, this section focuses primarily on the neurobiology of
this disorder. For a review of AN and BN, see Ref. (148). Preclinical data
relevant to BED and obesity will also be described.
Epidemiology
BED has its own diagnostic code in the DSM-5 (12). The proposed diagnostic
features are very similar to the diagnostic features of SUDs and ICDs: recurrent
episodes, impaired control, and marked distress in relation to binge eating.
Individuals may make repeated unsuccessful attempts to stop binge eating, and
they may report that their binge eating has detrimental social and occupational
effects—two important criteria for SUDs. Over a quarter of clinicians report
often or always using addiction-based therapies for BED (149), further
suggesting phenomenological and clinical similarities between BED and SUDs.
Obesity, a common consequence of binge eating, is increasingly common.
Defined as “abnormal or excessive fat accumulation that may impair health”
(150), it is estimated that up to 36.5% of the US population meets the criteria for
obesity (151). Globally, estimates from 2008 suggest that 1.4 billion adults were
overweight and that at least 200 million men and 300 million women were obese
(150). Associated medical conditions include type II diabetes, stroke,
osteoarthritis, heart disease, and cancer (150,152). Frequently co-occurring
psychiatric disorders include depression, anxiety, personality disorders, and
lifetime SUDs (153). Features of GD among individuals with BED are
associated with decreased self-esteem and increased substance use problems
(154).
While there are strong links between BED and obesity (155), it is important
to note that obesity and addiction are not necessarily related and that for some
individuals, overeating is a relatively passive event that takes the form of liberal
snacking and eating large portions (156). BED may be a specific subtype of
obesity driven by a biologically based hyperreactivity to the hedonic properties
of food, coupled with an enhanced motivation to encourage appetitive behaviors
that is related to neurobiological differences in reward and control circuitry
(157–162).
Conceptualization and Treatment

Along with the recent rise in the prevalence of obesity, there has been a
concurrent rise in the number and diversity of treatment interventions. Such
interventions range from preventative interventions, such as the incorporation of
nutrition classes into school curriculums, to pharmaceutical interventions, such
as the administration of appetite-suppressing drugs and use of surgical
innervations like gastric bypass surgery. Because some treatment interventions
for obesity are highly invasive (eg, gastric bypass, jaw wiring), it is important to
examine and assess not only efficacy but also tolerability and impact on quality
of life. It is also important to understand the pathophysiology underlying the
disorder, particularly if individual differences contribute to selection of effective
interventions.
The Biology of Eating Behaviors

The hypothalamus (via regulatory neuropeptides such as leptin, cholecystokinin
(CCK), and ghrelin) is an important site for the maintenance of energy
homeostasis. Lesions to the ventromedial hypothalamus result in hyperphagia
and obesity, whereas lesions to the lateral hypothalamus (LH) result in
hypophagia and weight loss. This finding led researchers to conceptualize the
LH as a “feeding center” and the ventromedial nucleus as a “satiety center.” In
this “dual-center” model of eating behavior, the hypothalamus plays a central
role and hypothalamic function contributes significantly to homeostatic
regulation within a larger motivational network (163).
Leptin
Leptin, an adipose-derived hormone, is a chemical modulator involved in the
maintenance of energy homeostasis and feeding behaviors (164). Leptin is also
implicated in other reward-seeking behaviors (164,165) including SUDs (166).
Leptin acts as a peripheral metabolic cue within the central nervous system to
modulate neuronal activity in brain areas involved in appetite control, including
the hypothalamus. Administration of exogenous leptin increases energy
expenditure and reduces hyperphagia and obesity in genetically leptin-deficient
mice and humans (ob/ob) (167). However, leptin deficiency syndrome is
extremely rare in humans (168). A recent fMRI study investigated three adults
with genetically mediated leptin deficiency 5 and 6 years post–leptin
replacement treatment. A longer duration of replacement treatment was
associated with increased activation in a ventral portion of the posterior
cerebellum in response to food images, whereas decreases in body mass were
associated with decreased activation in this area (169). Another fMRI study
similarly presented visual food and nonfood stimuli during a fasting state and a
fed state, both before and after leptin treatment, to two adolescents. Results
yielded significant behavioral and neural response changes between conditions.
When participants rated their level of preference for specific foods presented,
leptin administration was associated with decreased preference ratings during the
fed condition. Whereas activation in the NAcc and caudate nucleus of the
striatum was positively correlated with preference ratings in both the fed and
fasting conditions prior to leptin treatment, subsequent to leptin treatment striatal
activation was only positively associated with preference ratings in the fasting
condition (170). These data demonstrate extrahypothalamic action of exogenous
leptin and suggest that leptin may help to encode palatability.
Leptin and DA-Regulated Reward Processing

Mesolimbic reward pathways may play an important role in eating behaviors.
Increased activation of brain regions implicated in SUD—such as the OFC,
insula, striatum, and midbrain—has been observed subsequent to the
consumption of palatable food (171). Differential striatal activation in response
to food has also been reported in obese individuals in comparison to healthy
control subjects. An fMRI study of 13 obese females and 13 female controls
found that obese (vs. control) females selectively activated the dorsal striatum in
response to images of high-calorie foods (172). Moreover, in response to high-
calorie food stimuli, body mass index (BMI) was predictive of dorsal striatum,
anterior insula, claustrum, posterior cingulate, and postcentral and lateral OFC
activation (172). A separate study found that obese versus lean individuals
showed elevated corticostriatal responses to favorite-food cues, with thalamic
activation mediating the relationship between insulin resistance and food craving
in the obese but not in the lean individuals (173). Based on previous reports of
lowered DA levels in AN (174), one study investigating potential striatal
differences found that whereas healthy control subjects displayed differential
ventral striatal activation for rewards versus losses in a monetary reward task,
women who had recovered from anorexia showed no activation differences for
wins and losses, suggesting a reduced experience of reward (175). A more recent
study reported increased striatal activations to both pleasant and aversive food
stimuli among women recovered from anorexia (vs. healthy controls), further
suggesting that alterations in reward processing may be implicated in the
pathophysiology of disordered eating behaviors (176).
Preclinical research using pharmacological and genetic knockout strategies
suggests that D2 receptor blockade attenuates the acute hypophagic effect of
leptin in fasted mice (177). A reduced availability of DA D2 receptors in the
striatum has been reported in individuals with SUDs (178,179) and in obese
individuals, with receptor availability negatively correlated with BMI (180,181).
Preclinical research has demonstrated that knockdown of striatal DA D2
receptors rapidly accelerates the development of addiction-like reward deficits
and the onset of compulsive-like food seeking in rats (182). Together, these data
suggest dysregulated striatal function in eating disorders that at least in part
reflects dysregulated DA function.
Whereas leptin-modulated hypothalamic activity has been well documented,
research suggests that leptin acts directly on other brain regions, including the
substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of the
midbrain. DA neurons in the VTA and SNc project to the striatum and are
implicated in reward, motivation, and addiction. Preclinical data (183) have
demonstrated that DA neurons within the VTA express mRNA encoding for both
leptin and insulin receptors. Exogenous leptin administration to the VTA results
in a decrease in food consumption, and intravenous exogenous leptin
administration reduces the firing of VTA DA neurons (184). The expression of
mRNA encoding the long form of the leptin receptor (ObRb) has additionally
been reported in regions including the hippocampus, brain stem, cortex,
thalamus, cerebellum, and substantia nigra (185). Leptin has additionally been
reported to enhance synaptic plasticity in brain regions such as the hippocampus
(186).
Preclinical research using self-administration of electrical brain stimulation
of reward (BSR) technology suggests that leptin influences drug-taking
behaviors. An investigation by Fulton et al. (187) found increased BSR in
response to fasting conditions, which was attenuated by direct exogenous leptin
administration. A different study found that leptin-deficient ob/ob mice have a
lessened locomotor response to amphetamine administration, which is corrected
by leptin administration (187). These data suggest that, in addition to its
metabolic function, leptin may help to modulate mesolimbic reward circuits that
may relate to both palatability and substance use.
Orexins
Partially modulated by adipose-derived hormones such as leptin and ghrelin, the
hypothalamic neuropeptides orexin-A and orexin-B—also referred to as
hypocretin 1 and hypocretin 2—are important modulators of eating behavior and
help to maintain energy homeostasis. The hypothalamus is the primary site of
hypocretin-containing neurons, though these neurons project to other brain
regions (188–190). Orexin administration has been demonstrated to increase
feeding behaviors (189), while orexin antagonists have been shown to impair
operant responses to food reinforcers (191) in preclinical populations.
Preclinical research has demonstrated that administration of orexin-A
reinstates cocaine-seeking behaviors in a dose-dependent manner (192).
Administration of orexin-A was also associated with increases in BSR,
suggesting a negative regulation of reward circuits (192), consistent with orexin
neurons’ activation in chronic morphine administration and precipitated
morphine withdrawal (193). Similar research has demonstrated that the
administration of an orexin receptor agonist abolishes reinstatement of cue-
induced alcohol-seeking (194) and heroin-seeking (195) behaviors in rodents,
further implicating orexin in substance-seeking behaviors.
Preclinical research also indicates a significant increase in hypothalamic
orexin-containing neurons subsequent to preference conditioning for food,
cocaine, or morphine, suggesting important similarities between the
development of food and drug preferences (196). Whereas the number of orexin-
containing neurons was positively correlated with increases in preference, no
such correlations were found for any other type of hypothalamic neurons. This
study additionally reported reinstatement of morphine preference subsequent to
direct orexin administration to the VTA, one of the brain regions receiving
projections from hypothalamic orexin neurons (196).
Orexin may directly influence DA neurons in the VTA. Pharmacological
blockade of orexin-1 receptors (Ox1r) within the VTA—but not within the
paraventricular thalamus—dose-dependently attenuated cue-induced
reinstatement of cocaine seeking (197). Direct administration of orexin-A or
orexin-B produces locomotor-enhancing effects in mice that were prevented by
prior administration of a DA receptor antagonist (198). The same study
additionally demonstrated a lack of hyperlocomotion and a significantly lessened
increase in DA in response to morphine (198). Increases in PFC DA subsequent
to orexin-A administration to the VTA have also been reported (199). Together,
these data suggest that orexin may directly influence mesolimbic DA pathways
implicated in reward and drug addiction. However, further research investigating
the relationship between orexinergic and dopaminergic signaling in clinical
populations is needed.
Ghrelin
Ghrelin is a gastrointestinal hormone that helps to maintain energy homeostasis
and may contribute importantly to the initiation of eating. Unlike leptin and
orexin, which are anorexigenic, ghrelin is orexigenic and increases food intake
and body weight (200). One study measured ghrelin levels in the plasma of
healthy controls during a 24-hour period and found significant increases in
ghrelin levels prior to meal initiation followed by significant decreases after
consumption (201). Reduced levels of circulating ghrelin have been reported in
obese individuals, with an inverse correlation between BMI and ghrelin levels
observed (202). Interestingly, preclinical research suggests that whereas ghrelin
administration increases the motivation to eat, it does not alter perceived food
palatability (203).
Although ghrelin is primarily synthesized in the stomach, recent research
suggests that it may also mediate feeding behaviors via direct action on certain
brain regions. Preclinical research has identified a ghrelin receptor, growth
hormone secretagogue 1 receptor (GHSR), in the hypothalamus and VTA.
Ghrelin has been linked to increased synapse formation and DA turnover in the
NAcc (204). Administration of exogenous ghrelin in the VTA prompted feeding
behavior, and GHSR antagonist administration reduced feeding subsequent to
food deprivation (204). Direct administration of ghrelin into the VTA, but not
into the NAcc, was reported to motivate behavior for sucrose reward in an
operant conditioning paradigm in rats, suggesting that ghrelin signaling within
the VTA contributes to incentive-motivated behavior for a food reward (205).
Ghrelin administration–induced increases in motivation to eat are eliminated
following pretreatment with a DA D1 receptor antagonist, suggesting that the
orexigenic effects of ghrelin are mediated by DA signaling (203). Conversely,
ghrelin-deficient mice display attenuated responses to chronic and acute cocaine
administration, indicating that dopaminergic neurotransmission is disrupted by
deletion of the ghrelin gene (206). Overall, these findings suggest that ghrelin
may help to modulate the warding properties of food via interaction with DA
neurons.
The Nucleus Accumbens: Opioid and Endocannabinoid

Encoding of Palatability
Research suggests that opioid receptors in the NAcc region of the ventral
striatum may be particularly important for the encoding of food palatability.
Preclinical research suggests that DA release in the NAcc modulates excitatory
NAcc neuronal activity in response to previously learned reward-associated
cues, thereby increasing the likelihood of cue responsiveness (eg, performance
of behaviors learned via operant conditioning) (207). Stimulation of NAcc
opioid receptors has been found to increase food intake (208). Administration of
opioid receptor antagonists, such as naloxone or naltrexone, extinguishes
previously established preferences for sweetened versus unsweetened water in
rats, whereas morphine has been demonstrated to enhance palatability and
preference for sweet food (208,209). Importantly, such preclinical data
demonstrate opioid involvement in the palatability—or reward value—encoding
of food that does not appear to directly affect caloric intake. Rather, the opioid
system may be involved in general reward processing, as opposed to specific
appetitive control. These data nonetheless suggest shared neurobiological
mechanisms in eating and substance use behaviors. Despite evidence implicating
the opioid system in eating behaviors, pharmaceutical challenge studies of
opioid receptor antagonists such as naltrexone have yielded equivocal results in
human populations, and further research is needed to establish appropriate
pharmacotherapies for the treatment of BED. However, the stimulant
lisdexamfetamine has received FDA approval in the United States for the
treatment of BED (210).
Preclinical research has identified two distinct populations of NAcc neurons
responsive to food consumption: a group of neurons displaying primarily
excitatory responses to increased palatability (ie, increased sucrose) and a
separate group of neurons displaying primarily inhibitory responses prior to
initiation of feeding behaviors that does not appear to be related to palatability
(211). This finding is consistent with other preclinical research demonstrating
increases in nonappetitive food intake subsequent to NAcc inhibition (212). One
possible interpretation of these data is that—in addition to neurons encoding for
reward—a group of NAcc neurons may also be implicated in general habit
formation or basic motor control of feeding behaviors, independent of
palatability, although this hypothesis requires further testing. These data further
support the hypothesis that the NAcc is an important brain region for the
encoding of palatability as well as the initiation of feeding responses and
highlight similarities between eating and substance use behaviors.
Human and animal studies also implicate the endocannabinoid system
(composed of cannabinoid receptors, endocannabinoids, and associated
enzymes) in eating behaviors (213,214). The endocannabinoid system is
composed of two endogenous ligands, anandamide (arachidonoylethanolamide)
and 2-arachidonoylglycerol (2-AG), and two cannabinoid receptors, CB1 and
CB2 (215). Cannabinoid receptors in the NAcc have been implicated in
appetitive behavior.
Preclinical research suggests that CB1 receptors partially mediated by leptin
(216) are involved in the presynaptic modulation of release for the
neurotransmitters GABA, glutamate, DA, noradrenaline, and serotonin
(213,217) and has identified cannabinoid receptors (CB1/2) in the limbic
forebrain, striatum, and NAcc (reviewed in Ref. (218)). Colocalization of opioid
and CB1 receptors in the striatum has also been reported (reviewed in Ref.
(218)). Preclinical investigations have additionally reported increases in feeding
behaviors subsequent to administration of delta9-THC and anandamide (an
endogenous cannabinoid neurotransmitter) (reviewed in Ref. (218)).
Cannabinoids have long been associated with rewarding psychotropic effects and
are additionally associated with increases in food intake. In addition to
cannabinoid-induced increases in feeding behaviors, studies have implicated
endogenous cannabinoids in the experience and encoding of food-associated
reward. For example, direct anandamide administration to the NAcc shell has
been found to significantly enhance “hedonistic” reward and increase feeding
behaviors in rats (218). Elevated anandamide blood levels have been reported in
individuals with AN and individuals with BED, whereas no such elevation has
been reported in individuals with BN (215). Interestingly, a recent study suggests
that endocannabinoid administration increased gustatory nerve response to
sweeteners in a concentration-dependent manner without affecting responses to
other tasting compounds (eg, salty, sour, bitter, and savory) (219). The
cannabinoid 1 receptor (CB1R) is thought to be a promising drug target for
antiobesity medication, and the CB1R antagonist/inverse agonist, rimonabant,
has been shown to significantly reduce body weight in humans; however, it is
associated with psychiatric side effects including anxiety, depression, and
suicidal tendencies (220,221). Recent preclinical research suggests that the
neutral CB1R antagonist NESS0327 is as effective as rimonabant in reducing
weight gain and food intake and lacks potentially harmful effects on anxiety and
motivation (222).
Prefrontal Cortex
Research from neuroimaging, neurocognitive, and lesion studies implicates
prefrontal cortical modulation of eating behaviors. Frontotemporal dementia
(FTD), a degenerative disorder involving atrophy of frontal, insular, and
temporal cortical regions, is characterized by behavioral changes in eating and
sexual behaviors (223) as well as deficits in insight, empathy, and social
interaction (223,224). Clinically reported changes in eating behaviors associated
with FTD include increases in weight, food cravings/obsessions, and gluttony
(224). Similarly, a recent study found that individuals with FTD meeting criteria
for “gluttonous” overeating during “all-you-can-eat” 1-hour meal sessions had
significantly increased atrophy of the OFC, right ventral insula, and striatum
(225).
Evidence derived from positron emission tomography (PET) research
additionally suggests a relationship between frontal lobe activity and eating
behaviors. In weight-loss studies, “successful” as compared to “non-successful”
weight-loss dieters/maintainers had significantly greater activation in dorsal PFC
(DPFC), dorsal striatum, and anterior cerebellar lobe brain regions following
meal consumption (226) and food visualization (227). Conversely, unsuccessful
dieters had significantly greater OFC activation following meal consumption
(226). These data suggest differential modulation of eating behaviors by
prefrontal regions. Further investigation is required to fully understand
interactions between PFC regions in relation to eating behaviors.
Consistent with the finding that greater dietary restraint is negatively
correlated with OFC activation and positively correlated with DPFC activation,
one randomized, double-blind, parallel group study using repetitive transcranial
magnetic stimulation found reduced self-reported craving sensations in response
to exposure to craving-inducing foods subsequent to left dorsolateral prefrontal
cortex (dlPFC) stimulation (228). dlPFC stimulation has also been reported to be
effective in reducing cravings for nicotine, alcohol, and cocaine, suggesting
potentially similar neurobiological mechanisms for food and drug craving
(reviewed in Ref. (229)).
Neurocognitive research additionally implicates frontal lobe involvement in
binge eating. Similar to impulse control–related disorders (eg, SUDs, GD),
deficits in decision-making have been reported in BED and obesity. In a sample
of 41 healthy adult women, a tendency to overeat in response to stress and
higher BMI both significantly predicted poorer IGT performance (230). In other
studies, obese (vs. nonobese) individuals also performed significantly worse on
the IGT and showed no improvement in performance over time (230–232).
Similar decision-making deficits have been reported in both AN and BN.
Individuals with AN have been reported to perform significantly worse on the
IGT and displayed significant reduction in skin conductance response in
comparison to healthy controls and recovered AN patients (ANR) (233). In
contrast, Liao et al. (234) reported that while BN individuals similarly performed
poorly on the IGT, unlike individuals with AN, they showed no reduction in skin
conductance response. Similar performance deficits among individuals with BN
were also reported in a study using the Game of Dice Task (235), a decision-
making assessment that, unlike the IGT, provides explicit information of
reward–loss contingencies (236).
Serotonin (5-HT)
Increases in both exogenous and endogenous serotonin (5-HT) are associated
with a reduction of food intake and weight gain and an increase in energy
expenditure (237). In relation to eating behaviors, research has focused on 5-HT
and the hypothalamus. 5-HT neurons located in the dorsal raphe nucleus receive
direct projections from hypothalamic orexin neurons and express orexin-A and
orexin-B receptors (reviewed in Ref. (238)). Hypothalamic 5-HT may in part
mediate the experience of satiety. Medial hypothalamic 5-HT is implicated in the
temporal management of eating behavior, in particular with meal termination, as
opposed to initiation. Preclinical research has demonstrated that d-fenfluramine
(d-FEN)—also known as “fen-phen” when combined with phentermine—an
exogenous agent that increases 5-HT release while also blocking reuptake, may
exert its anorexigenic effects via 5HT2C receptor activation of
proopiomelanocortin (POMC) neurons in lateral hypothalamic regions (239).
Further research is needed to establish the precise role of the central
melanocortin system in the regulation of food intake. Such data may help to
develop alternative pharmacotherapies for BED and other eating disorders (239).
5-HT is also thought to be implicated in food preference. For example,
preclinical studies have demonstrated that the injection of either exogenous 5-
HT or drugs that increase 5-HT availability (such as fluoxetine) into the medial
hypothalamus selectively inhibits carbohydrate intake but has no significant
effect on fat or protein intake (240). Conversely, elevated levels of tryptophan
(TRP), a 5-HT amino acid precursor and hypothalamic 5-HT, are associated with
high-carbohydrate intake (reviewed in Ref. (237,241)).
SSRIs have been shown to be efficacious in treating eating disorders with
fluoxetine approved by the Food and Drug Administration for the treatment of
BN and sibutramine approved for the treatment of obesity (242). Some research
suggests that SSRIs are effective in targeting binge eating, psychiatric, and
weight symptoms (243), although the effectiveness and duration of these
medications remain under debate. In an open-label study, Leombruni et al.
(244,245) reported that BED patients who display decreased binge eating and
weight loss following initial SSRI administration maintained these beneficial
effects for 6 months with continuation of SSRI treatment. In a randomized,
double-blind, 12-week study of escitalopram versus placebo for the treatment of
individuals with comorbid BED and obesity, individuals receiving high-dose
escitalopram treatment had significantly greater reductions in weight, BMI, and
total global illness severity (246). However, no significant between-group
differences were found for the variables reduction of binge episodes, reduction
of days with a binge episode, and reduction of obsessive–compulsive features of
BED. In a 2-year follow-up of fluoxetine-treated individuals with BED, no
significant improvements in BED symptoms were reported, despite significant
improvements in depressive symptoms (247).
Conclusion
Binge eating and comorbid obesity are increasingly common phenomena with
wide-ranging public health implications. Recent neurobiological findings, such
as the involvement of the adipose-derived hormone leptin in the dopaminergic
reward system, suggest that BED is a brain-based disorder that may share many
of the same neurobiological features as SUDs. Such findings have important
treatment implications, and further investigation is required in order to optimize
treatment interventions.
COMPULSIVE SEXUAL BEHAVIOR

As described in Chapter 46, CSB (termed problematic sexual behavior (PSB)
therein) is characterized by excessive engagement in normative sexual
behaviors. Not included in the DSM-IV or DSM-5 (but being considered as an
ICD in ICD-11 (248)), CSB is also referred to as sex addiction, hypersexual
disorder (the proposed but rejected diagnostic entity for DSM-5), or sexual
impulsivity (249).
Clinically relevant sexual behaviors may be divided into paraphilic and
nonparaphilic behaviors. In paraphilic sexual behaviors, there is a disturbance in
the object selection (eg, an animal, unwilling person, inanimate object). In
nonparaphilic sexual behaviors, the individual engages in socially normative
sexual behaviors in an excessive, obsessive, or compulsive manner, without a
disturbance of object choice. Paraphilic disorders are a distinct category of
disorders, already included in the DSM-5, and are outside the scope of this
chapter.
Epidemiology
There has been no systematic epidemiological study of CSB, although estimates
of 5% to 6% in the adult population have been reported (250,251). The majority
of research on CSB has been conducted using predominantly male clinical
populations. Co-occurring mood disorders (eg, early-onset dysthymia), anxiety
disorders, SUDs, ICDs, and ADHD have been reported in association with CSB
(252,253).
Phenomenological similarities between CSB and SUDs have been described
(249). Individuals suffering from CSB often report feeling “out of control.”
Estimates of co-occurrence rates for SUDs and CSB range from 25% to 71%
(252). CSBs are aimed at reward seeking and anxiety reduction. Individuals with
CSBs report feelings of regret and fear over losing loved ones or employment as
a result of their behaviors (254).
Defining the Disorder

Nonparaphilic impulsive or compulsive sexual disorders are not specifically
listed in the DSM-5. As with ICDs, CSB can be conceptualized along an
impulsive–compulsive spectrum or as a substance use disorder (249,252,255).
Coleman (256) has identified seven distinct CSB categories, all with their own
unique constellation of symptoms: compulsive cruising and multiple partners,
compulsive multiple love relationships, compulsive sexuality in a relationship,
compulsive use of erotica, compulsive autoeroticism, compulsive use of the
Internet, and compulsive fixation on an unattainable partner. When assessing
sexual behaviors, Kafka (257) redefined Kinsey et al.’s (258) original frequency
measure to the total sexual outlet as number of orgasms/number of weeks—a
total sexual outlet score ≥7 is associated with both paraphilic and nonparaphilic
(ie, CSB) disorders. Other instruments, such as the Minnesota Impulsive
Disorders Inventory (259) and clinician-designed “hypersexuality” (ie, CSB)
questionnaires (260), more closely resemble the diagnostic criteria for SUDs and
GD: maladaptive preoccupation with sexual behaviors/thoughts; repetitive
sexual fantasies causing distress or associated with a loss of control; repetitive
sexual urges causing distress or associated with a loss of control; and repetitive
engagement in sexual behaviors (including masturbation, telephone sex lines,
and phonography) causing distress or associated with a loss of control.
Neurocircuitry
In human and preclinical populations, bilateral temporal lesions are associated
with placidity, hyperorality, visual agnosia, and hypersexuality (261). Together,
this constellation of symptoms has been termed Klüver-Bucy syndrome and has
also been observed in amygdala-lesioned patients (252). Extremely rare in
humans, Klüver-Bucy syndrome’s associated hypersexuality, although
infrequent, suggests an involvement of temporal lobe function in CSB and other
paraphilia-related disorders. Klüver-Bucy syndrome is most commonly
associated with Alzheimer disease, herpes simplex encephalitis,
ischemia/anoxia, and temporal lobectomies.
Functional imaging studies of CSB have been recently published (262), with
findings suggesting significant parallels with addiction. Attentional biases
toward sexual cues have been linked to CSB and neural regions implicated in
motivational processes (263). During exposure to sexual cues, men with CSB, as
compared to those without, activate to a greater degree brain regions previously
implicated in reward and craving, with subjective responses suggesting greater
wanting than liking, consistent with incentive salience models of addiction
(264). Among men with problematic pornography use as compared to those
without, greater ventral striatal activation to cues associated with sexual reward
images was observed, but no between-group differences were associated with
monetary cues or sexual or monetary reward outcomes (265). Furthermore, the
differences in ventral striatal activation to sexual versus monetary cues were
associated with faster reaction times to receive sexual rewards and out-of-
magnet measures relating to hypersexuality and masturbation frequency (265).
Thus, findings link to clinical characteristics of CSB and theoretical aspects of
addiction and habit formations where salience may shift from rewards to cues.
Clinically, a case report suggested naltrexone’s efficacy in reducing craving
relating to CSB (266), similar to findings in gambling and alcohol addiction.
Neurostructure
There has been a DTI study of white matter microstructures in CSB. Miner et al.
(267) reported significantly higher mean diffusivity in a superior frontal region
among individuals with CSB in comparison to controls. Correlational analyses
revealed a significant negative association between fractional anisotropy (FA)
within an inferior frontal region and self-reported impulsivity. However, given
the small sample size of this study (ie, eight patients with CSB and eight
controls), further research is needed.
Neurochemistry
DA, 5-HT, NE, and the opioid system contribute to human sexual behavior,
though systematic studies of their involvement in CSB are lacking. Open-label
prescriptions of lithium, tricyclic antidepressants, SSRIs, nefazodone,
naltrexone, and atypical antipsychotics have all been used to treat CSB (268),
but their efficacy in treating CSB remains to be systematically examined. At
present, most of the data on pharmacological treatment for CSB are only from
individual case reports, and more research is needed to identify empirically
validated pharmacotherapies.
5-HT is implicated in sexual functioning and desire, and sexual
dysfunctions, such as decreased libido, anorgasmia, and delayed ejaculation, are
reported as adverse effects of SSRI treatment (250,269). There is mixed
evidence to support the efficacy of SSRIs in treating CSB symptoms. In a
randomized clinical trial, homosexual men with sexually compulsive behavior
reported a greater reduction reduced sexual desire after taking citalopram,
without a lessening in sexual satisfaction, than did individuals taking placebo
(270). It is presently not clear whether the effectiveness of SSRI administration
in reducing CSB symptoms can be attributed to an actual reduction of sexual
thoughts or to the sexual side effects of the medication (250). Positive results
have been noted with nefazodone, a phenylpiperazine antidepressant that
antagonizes 5-HT receptors and influences 5-HT and NE reuptake, in reducing
sexual thoughts without the presence of substantial sexual side effects over the
long term (250). Because sexual side effects may deter CSB patients from
continuing SSRI treatment, nefazodone may be particularly beneficial in treating
CSB. However, controlled trials are needed to further determining the efficacy
and tolerability of nefazodone in treating CSB.
Pharmacological tolerance to SSRI treatment has been reported in men with
CSB and ADHD co-occurs with CSB. Kafka and Hennen (271) examined the
effect of psychostimulant augmentation during SSRI treatment in a sample of
men with paraphilic or paraphilia-related (eg, CSB) disorders. They found a
significant reduction in paraphilic or paraphilia-related behaviors in response to
SSRI treatment alone and also reported a significant improvement subsequent to
methylphenidate SR (sustained release). These preliminary data suggest an
additive effect of methylphenidate administration in CSB populations that may
help to counteract pharmacological tolerance to SSRIs, and they additionally
implicate a dysregulation of DA, 5-HT, and NE systems in CSB. The SSRI
paroxetine was explored in the treatment of three men with CSB relating to
pornography use and while reductions in pornography use were observed, non-
pornography-related problematic sexual behaviors emerged. (272) Given these
findings, controlled trials with careful monitoring of a range of sexual behaviors
are needed to examine the efficacy and tolerability of these medications in
treating CSB.
The opioid system may also play a role in sexual behaviors (eg, in mediating
orgasm and arousal), and the endogenous opioid system may be dysregulated in
CSB. In a randomized, double-blind crossover design, naltrexone (25 mg/d), an
opioid receptor antagonist, or placebo was administered to a sample of 20
sexually active men over a 3-day time period (273). After 14 days, participants
were administered either naltrexone or placebo (ie, whichever they did not
receive in the initial trial). As assessed via subject self-report, naltrexone
administration was associated with increased sexual arousal, greater frequency
of orgasms, and orgasm intensity in response to masturbatory behaviors.
Topiramate, an anticonvulsant hypothesized to partially inhibit GABAergic input
into the NAcc in a similar fashion to opioid antagonists (274), has also been
shown alleviate symptoms of CSB although these effects were not maintained
following topiramate discontinuation (268). Conversely, preliminary open-label
studies of opioid receptor antagonists in CSB populations suggest possible
efficacy at high doses; for example, administration of naltrexone at 150 mg/d
(275) and 100-200 mg/d (276) have been reported to successfully reduce CSB
symptoms and decrease sexual fantasies and masturbation. Together, these
potentially contradictory findings suggest the involvement of endogenous
opioids in CSB, although the precise relationship remains unclear. Other factors,
including differences in patient populations and dosing durations, also warrant
consideration.
Increased sexual desire and impulse control behaviors have been observed in
patients with PD or restless leg syndrome (RLS) taking dopaminergic
medications (110,277). Voon and Fox (260) estimated that 2.4% of PD patients
taking DA agonists meet the criteria for hypersexuality or pathological sexual
behavior. In a study of 70 RLS patients without comorbid PD, 5% of
respondents reported a high level of sexual desire and 4% reported that their
desire had increased subsequent to taking dopaminergic medication
(pramipexole, ropinirole, levodopa, and pramipexole) (277). None of the patients
with high levels of sexual desire had a personal or family history of CSB or
sexual paraphilia. However, impulse control behaviors (including
hypersexuality) have been associated with demographic and clinical features of
PD independent of medication, supporting the notion that multiple factors
contribute to the development of ICDs in PD (110,278). Further research is
needed to examine the potential role of DA in the pathophysiology of CSB and
other sexual behaviors in PD and RLS as well as in individuals without these
disorders, particularly as DA pathology is central to PD.
Conclusion
CSB has been clinically acknowledged for years but is not listed in the DSM-5,
although it is being considered for ICD-11. Like other behavioral addiction, CSB
is negatively associated with distress and may interfere with personal and
professional life. Little is currently known about the neurobiology of CSB, and
further research studies are needed to determine effective therapeutic
interventions.
PROBLEMATIC INTERNET USE

Not currently included in the DSM-5, PIU or “Internet addiction” has been
underresearched and rarely addressed clinically. PIU may be characterized by
excessive or poorly controlled urges and a maladaptive obsession with the
Internet (244,279) (see also Chapter 47). While moderate Internet use may
enhance one’s quality of life by widening social circles and enhancing
psychological well-being (280–282), excessive Internet use may be problematic
and impact negatively on daily function, family relationships, and emotional
stability (280,281,283). Moreover, PIU may be positively associated with SUDs,
incarceration and legal troubles, and poor physical and mental health
(279,284–287). As with other ICDs such as compulsive shopping, PIU involves
excessive engagement in socially normative activities. As such, it may be hard to
identify, and patients may be reticent to disclose excessive Internet use
behaviors, due to embarrassment, lack of awareness, or ambivalence over
reducing their use. As described under the video-gaming section, the DSM-5
focused on video gaming on the Internet to generate criteria for IGD, currently in
section III of the DSM-5. Similarly, proposed criteria for gaming disorder in the
ICD-11 exist, with the gaming disorder to be grouped together with GD and
SUDs.
Epidemiology
There are no uniformly agreed-upon diagnostic criteria for PIU. Definitions of
PIU have often been based on DSM-IV criteria for PG (288–290). Of these,
Young’s Internet Addiction Scale (291) is often used and has demonstrated
sufficient reliability (292–294). Based on the DSM-IV definitions of SUDs and
PG, Young (291) proposed the following criteria for “Internet addiction”:
withdrawal, tolerance, preoccupation with the Internet, longer than intended
spent on the Internet, risk to significant other relationships and/or employment,
lying about Internet use, and repeated, unsuccessful attempts to stop Internet use.
The lack of a universal assessment tool may contribute to the wide range of
prevalence estimates reported among adolescents (4.0% to 19.1%) and adults
(0.7% to 18.3%) (reviewed in Ref. (295)).
In terms of comorbidity, PIU frequently co-occurs not only with SUDs
(296–298) but also with various psychiatric conditions including impulse-
control, mood, and personality disorders (290,292,299,300).
Neurocircuitry
While evidence remains scarce and limited, there is emerging research
examining brain function among individuals with PIU. In an fMRI study,
increased resting state regional homogeneity involving the right frontal region,
left superior frontal gyrus, right cingulate gyrus, bilateral parahippocampus, and
other regions was observed among PIU individuals (vs. controls) (301). Other
evidence suggests differences in brain function during cognitive tasks. Greater
activation of the anterior and posterior cingulate cortices during the Stroop
color–word interference task has also been observed (302). Interestingly, greater
ACC activation was associated with slower incongruent reaction time and more
severe scores on the Young’s Internet Addiction Scale across all participants
(302). In a monetary gain and loss guessing task, increased activation of the
OFC to gain trials and decreased ACC to loss trials was observed among PIU
compared to controls, suggesting sensitization to reward and desensitization to
loss (303).
Neurostructure
A VBM study reported decreased gray matter density in the left ACC, left
posterior cingulate cortex, left insula, and left lingual gyrus among individuals
with PIU in comparison to age- and gender-matched comparison participants
(304). Similarly, an independent study reported among adolescents with
“Internet addiction” relatively decreased gray matter volumes in the left ACC—
as well as in regions of the dorsolateral and orbitofrontal PFC, supplementary
motor area, and cerebellum (305).
FA—a widely used measure of white-matter integrity based on DTI—was
increased within a region of the left internal capsule and decreased within a
region of the right parahippocampal gyrus among adolescents with “Internet
addiction” (vs. controls) (305). By contrast, Lin et al. (306) reported widespread
impairments in white-matter microstructures—as indexed by decreased FA and
increased radial diffusivity—encompassing callosal, association, and projection
fiber tracts among adolescents with “Internet addiction.” Together, these data
suggest involvement of white-matter microstructures in the pathophysiology of
PIU. However, given the differences in anatomical loci reported between studies,
further research into the precise relationship between scalar indices of white-
matter microstructural integrity (eg, FA) and PIU are warranted.
Neurochemistry
There have been ligand-based studies of dopaminergic functioning among
individuals with PIU. A small-scale single-photon emission computed
tomography (SPECT) study reported reduced DA transporter expression within
the striatum among young adult males who used the Internet almost every day
and spent more than 8 hours per day online, compared to matched controls
(307). Another small-scale study using [11C]raclopride during PET scanning
reported that adult males with PIU had reduced DA D2-like receptor availability
in the bilateral caudate and left putamen compared to controls and that the
degree of DA receptor availability was inversely correlated with the severity of
PIU (308). These preliminary findings suggest that PIU may be associated with
dopaminergic neural systems in a fashion similar to substance-related addiction.
Genetic Polymorphisms in PIU

The short allelic variant of the gene encoding the serotonin transporter (SS-
5HTTLPR) has been reported to be more prevalent among 91 adolescent males
with PIU compared to 75 matched controls (309). Within the PIU group, the
authors reported that those with the SS-5HTTLPR showed higher harm
avoidance and scored higher on Young’s Internet Addiction Scale compared to
those expressing other 5HTTLPR allelic variants. The T-variant (CC genotype)
polymorphism of the nicotinic acetylcholine receptor subunit alpha-4
(CHRNA4) gene has also been implicated, with increased frequencies among
individuals with PIU compared to controls; further analyses revealed that this
finding was driven by females, suggesting sex-specific genetic effects (310).
Replication of these findings is needed in future studies before definitive
conclusions can be drawn.
Gender Differences
As with SUDs, significant gender differences have been reported in PIU. In a
Taiwanese study of Internet behaviors among adolescents (n = 2114), higher
levels of Internet addiction were associated with higher rates of ADHD and
depression across genders. However, higher rates of aggression were associated
with increased severity of PIU only among males (311). Social phobia was also
associated with Internet addiction, although not significantly after accounting for
ADHD, depression, and hostility symptoms. These data suggest that ADHD,
depression, and aggression may be vulnerability factors for PIU and that social
phobia may be a negative consequence of PIU (311). Some data suggest that the
proportion of Internet users is slightly higher among men than among women,
with men being more likely to have PIU (312–314), although this gender gap has
not been observed consistently (315).
Conclusion
Although not currently included in the DSM-5, PIU is associated with significant
psychological distress and has been increasingly researched in recent years.
Preliminary evidence suggests neurobiological similarities with SUDs; however,
further research is needed to support this hypothesis.
PROBLEMATIC VIDEO-GAME
PLAYING/INTERNET GAMING
DISORDER
Although some (316) might argue that problematic video-game playing or
“video-game addiction” is part of PIU and both should be considered under the
umbrella term pathological technology use, the two conditions may relate to
different clinical and health-related characteristics and, as such, merit separate
consideration (see also Chapter 47). The term IGD has been introduced in
Section III of the DSM-5, with the rationale that Internet video gaming has been
associated with significant harms when played excessively but that further
research was warranted prior to making the entity a formal diagnosis. The entity
of gaming disorder is being considered for inclusion in the ICD-11. Whereas PIU
may encompass a broader range of Internet-related behaviors (eg, social
networking), IGD is both similar to and distinct from other behavioral addiction
such as GD and PIU in its availability and use of visual and auditory rewards,
and these differences may contribute to IGD’s unique features (317,318).
However, previous research on problematic video-game playing has often
included online games; thus, video-game findings cannot be clearly separated
from Internet findings based on existing data.
Epidemiology
IGD has been linked to low social competence, low academic performance, and,
in the case of violent video games, aggression or violence (295). Extreme cases
of IGD have been cited as a possible contributing factor in deaths in South Korea
(319) and the United States (320). Assessment tools for IGD were initially based
on the DSM-IV definitions for SUDs and PG (321–323), with more recent
assessment instruments for DSM-5 IGD (324). A range of prevalence estimates
has been reported for adolescent populations (4.2% to 20.0%), with published
adult estimates (11.9%) falling in this range (295).
Psychiatric comorbidities in individuals with IGD have been researched with
preliminary findings suggest links with ADHD (325), mood disorders (292,326),
and SUDs (326,327), though negative results have also been reported (328).
Neurocircuitry and Structure

The ventral striatum has been frequently implicated in fMRI studies of IGD. In
one MRI study, both structural and functional differences were observed in
frequent (>9 hours per week) compared to infrequent (≤9 hours per week)
gamers (329). Greater left ventral striatal gray matter volume was observed in
frequent as opposed to infrequent video gamers, and volume of this region was
negatively correlated with deliberation time during the Cambridge Gambling
Task. Activation in the same region was also greater during feedback of loss
compared to no loss during performance of a monetary incentive delay task
among frequent compared to infrequent video gamers.
Other brain regions have also been implicated in IGD. Among 19 healthy
male adults who played a novel video game for 60 minutes per day for 10 days,
increased activations to video game versus neutral stimuli were observed in the
left inferior frontal gyrus, left parahippocampal gyrus, right and left parietal
lobe, right and left thalamus, and right cerebellum (330). Greater activation of
the right OFC, right NAcc, bilateral ACC, medial frontal cortex, right dlPFC,
and right caudate in response to video-game cues has also been reported among
adult males who spent more than 30 hours per week playing World of Warcraft
(a Massive Multiplayer Online Role-Playing Game), in comparison to nonheavy
players (<2 hours per day) (331). Subsequent studies have similarly reported
greater activation in these regions among individuals with current IGD (332) and
among individuals in remission from online IGD (333) in response to video-
game cues, in comparison to controls.
While many early studies examined frequent versus infrequent players,
limiting the generalizability of findings to IGD, more recent studies have
examined individuals with IGD. These studies have suggested differences in
reward processing and control that at times have been linked to cognitive
processes and treatment outcome (334). For example, a resting state fMRI study
found that individuals with IGD as compared to those without had relatively
decreased functional connectivity within executive-control networks and that the
strength of connectivity was inversely linked to Stroop performance, a measure
of cognitive control (335). Individuals with IGD as compared to those without
also showed shorter reaction times and less activation of the ACC when
performing a risk-taking task (336). During exposure to gaming cues, individuals
with IGD as compared to those without showed differences in insula activation
that were related to treatment for IGD. Specifically, the individuals with IGD
who received a craving behavioral intervention that included elements of
cognitive behavioral therapy and mindfulness training as compared to those
undergoing test-retest assessment demonstrated decreases in Internet addiction
severity, hours of gaming, and craving responses to gaming cues (337). The
treatment group also demonstrated relatively increased activation of the insula to
gaming cues following treatment as compared to before and as compared to the
test-retest comparison group (337). Further, this region of the insula showed
relatively decreased connectivity with the lingual gyrus and precuneus following
treatment as compared to before treatment (337). In the same cohort, resting
state MRI data implicated regions of the OFC and posterior cingulate cortex,
with group receiving the intervention showing relatively deceased connectivity
between the OFC and hippocampus, posterior cingulate cortex and
supplementary motor area, and posterior cingulate and precentral gyrus (338).
These findings suggest a biological mechanism for how a promising treatment
for IGD might operate at a biological level. Based on these findings, models for
IGD based in part on those for GD and SUDs have been proposed (339,340).
Neurochemistry
In an early study using the D2-like DA receptor radioligand [11C]raclopride
during PET scanning, findings consistent with increased release of DA,
particularly in the ventral striatum, were observed following a 50-minute video-
game play in eight healthy adult males (341). A more recent study using SPECT
suggests that DA release in the ventral striatum during a motorbike riding
computer game (342) is comparable to that induced by psychostimulant drugs
such as amphetamine (343) and methylphenidate (344). Individuals with
frequent gaming (>30-hour StarCraft per week) reported decreased craving for
video-game play, reduced total game play time, and reduced cue-induced brain
activity in the dlPFC following 6 weeks of bupropion (a drug with
dopaminergic/noradrenergic reuptake blocking properties), compared to
pretreatment (345).
Genetic Polymorphisms in IGD

Limited research regarding genetic polymorphisms in IGD exists.
Polymorphisms of the TaqIA1 allele of the DRD2 receptor gene and Val158Met
in the catecholamine-o-methyltransferase (COMT) gene have been implicated in
preliminary studies of IGD. TaqIA1 and low-activity (COMTL) alleles were
more prevalent among 79 problematic Internet video-game players compared to
75 controls (346), and the DRD2 TaqIA1 allele was associated with reward
dependence among problematic Internet video-game players. Further research
with respect to the genetic factors relating to IGD is needed.
Gender Differences
While adolescent boys are more likely to endorse more IGD symptoms (325), a
recent study suggests that video gaming is associated with measures of
aggression and violence among adolescent girls. However, no associations with
negative health measures were observed among adolescent boys suggesting that
video gaming may be a normative behavior among boys, at least in the current
US culture. Research pertaining to gender-related differences in adults has
yielded mixed results (295).
Conclusion
Preliminary evidence suggests alterations in ventral striatal structure and
function among individuals with IGD and possible dopaminergic and
serotonergic involvement in video-gaming behaviors.
COMPULSIVE BUYING DISORDER

Classically referred to as “oniomania,” compulsive shopping or buying has been
clinically recognized for at least a century (347) (reviewed in Ref. (348)). It is
estimated that about 5% of individuals in the general population experience
compulsive buying disorder (CBD) (349), with higher estimates in psychiatric
populations (259). However, little is known about its pathophysiology or
treatment. Data suggest its classification as a behavioral addiction (350),
although some others contend that an ICD classification may be more
appropriate (351).
Neurocircuitry
An early imaging-based study examined individuals with CBD. Raab et al. (347)
compared blood oxygen level dependent in fMRI signal responses between
individuals with CBD currently undergoing treatment with a psychiatrist or
psychologist versus those of healthy controls during performance of a
multiphase purchasing task (352). During an initial product presentation phase,
CBD individuals showed stronger NAcc activity compared to controls. During
the subsequent price presentation phrase, CBD individuals showed attenuated
activation of the insula and ACC compared to controls. In contrast, individuals
with CBD had increased ACC activity while making purchasing decisions, in
comparison to controls. More recent studies suggest that constructs related to
addiction (eg, craving, decision-making, and other executive functions) hold
relevance for CBD (353).
Neurochemistry
Selective Serotonin Reuptake Inhibitors
Pharmacological studies suggest certain similarities with SUDs, in particular
with respect to the potential efficacy of naltrexone in CBD populations.
Consistent with findings from other studies conducted among individuals with
behavioral addiction such as GD, a substantial placebo effect has been reported
in pharmacological treatment studies of SSRIs for CBD. Positive results for
citalopram have been reported in a small open-label trial (354). However,
double-blind studies have reported no between-group differences in outcome
with fluvoxamine (355) and escitalopram (356). These findings from controlled
studies raise questions regarding the clinical utility of SSRIs in the treatment of
CBD.
Opioid Antagonists
There have been four case reports of successful naltrexone treatment in CBD
(357,358). Kim (357) has reported successful CBD treatment with naltrexone
(100 mg/d) in one individual with comorbid BN (which was also responsive to
naltrexone treatment). Grant (358) reported three cases of successful high-dose
naltrexone (100-200 mg/d) treatment for CBD.
Conclusion
CBD is associated with significant psychological distress, and preliminary
research suggests altered neurofunctional responses to shopping stimuli.
However, very few treatment studies exist. The availability of assessment tools
for CBD should aid in clinical and research efforts (359). Future research should
further explore the efficacy of medications such as naltrexone using double-
blind, placebo-controlled trials.
CONCLUSION
Research on the neurobiology of behavioral addiction has increased in recent
years, particularly in GD, IGD, and CSB. Existing research suggests that these
disorders share multiple features with SUDs and may be considered behavioral
addiction, although alternate conceptualizations also warrant consideration.
Additional research is needed to determine how specific behavioral addiction are
related to one another and to specific SUDs and how an improved understanding
of the biologies of these disorders may be translated into improved prevention
and treatment strategies.
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CHAPTER 45
Gambling Disorder: Clinical
Characteristics and Treatment
Jon E. Grant and Brian L. Odlaug
CHAPTER OUTLINE
Epidemiology
Assessment
Treatment
Gambling disorder, also called “pathologic(al) gambling,” is a psychiatric

disorder characterized by persistent and recurrent maladaptive patterns of
gambling behavior, which is associated with impaired functioning, reduced
quality of life, and high rates of bankruptcy, divorce, and incarceration (1).
Defined broadly as wagering money or something of value on an event with an
uncertain outcome, “gambling” and excessive gambling behaviors have been
reported for millennia across cultures and have been discussed in the medical
literature since the early 1800s (2). Gambling disorder, however, was recognized
by the American Psychiatric Association only in 1980 in their third edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-III) (3).
Currently classified in Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5), as a “substance-related and addictive
disorder,” the diagnosis of gambling disorder recommends that a person meets
four of the possible nine criteria listed for the disorder. These criteria include (a)
a preoccupation with gambling; (b) the need to gamble with higher amounts of
money (tolerance); (c) has tried unsuccessfully to stop or cut back on gambling;
(d) feels restless or irritable when not able to gamble; (e) gambles to escape from
a mood or problems; (f) chasing losses; (g) lies to family, friends, and others
about the amount or extent of gambling; (h) has lost or put into jeopardy a job,
educational, or other opportunities due to gambling; and (i) has needed others to
pay for finances due to gambling losses. Further, gambling must not be better
accounted for by a manic episode. The term problem gambling has been used to
describe forms of disordered gambling, sometimes inclusive and at other times
exclusive of gambling disorder. Problem gambling, like problem drinking, is not
an officially recognized disorder by the American Psychiatric Association.
The concept of behavioral addiction has some scientific and clinical heuristic
value but remains controversial. This is probably so because gambling disorder
is often resistant to treatment, and it remains unclear whether the methods of
traditional addiction treatment (group, 12-step participation, relapse prevention,
motivational enhancement, etc.) are superior, inferior, equivalent, or need to be
combined with those of psychiatric treatments (medication, cognitive–behavioral
therapy [CBT], psychotherapy). Nonetheless, evidence supports significant
phenomenological, clinical, epidemiological, and biological links with substance
use disorders (4,5). These data support the conceptualization of gambling
disorder as a “behavioral”—as opposed to a substance—addiction. Issues around
behavioral addiction were debated in the context of development of DSM-5 (6)
and ultimately led to gambling disorder shifting from its categorization in DSM-
IV as an “impulse control disorder not elsewhere specified” to a DSM-5
categorization in the “substance-related and addictive disorders.” Not only is
substance use disorders research likely to be illustrative for gambling disorder,
but the study of gambling disorder presents an opportunity to study addictive
behaviors without necessarily being confounded by neurotoxicity associated
with acute or chronic substance use (7). As such, it seems increasingly important
that individuals involved in the prevention and treatment of substance use
disorders have a current understanding of gambling disorder and the potential for
future research findings to guide prevention and treatment efforts for addiction in
general. In addition, the high prevalence and adverse impact of gambling
disorder among individuals with substance use disorder make it important for
those in the field. Further, important clinical differences based on severity of
gambling disorder are also imperative for the clinician to understand. Recent
research examining a sample of 574 patients with gambling disorder, sorted by
clinical severity, denoted that those with a moderate or severe form of gambling
disorder exhibited far worse quality of life, higher depressive and anxiety-related
symptoms, and increased nicotine use as compared to those in the mild gambling
disorder group (8). In order to afford more efficacious treatment to patients with
gambling disorder, understanding the clinical differences that may exist among
and between patients is of paramount importance.
EPIDEMIOLOGY
A range of prevalence estimates have been reported for gambling disorder
depending upon the time frame of the study, the instruments used to diagnose the
disorder, and the population examined. In the general population of the United
States, however, only four national studies and one meta-analysis of state and
regional surveys have examined prevalence estimates of gambling disorder. The
first national study in 1976 noted that 0.8% of 1749 adults contacted via
telephone survey had a significant gambling problem (9). Twenty years later, the
National Opinion Research Center at the University of Chicago conducted a
national telephone survey (requested by the National Gambling Impact Study
Commission) of 2417 adults and found a lifetime prevalence estimate of 0.8% of
gambling disorder and an additional 1.3% of problem gambling (10). Another
national telephone survey of 2628 adults found that 1.3% had current gambling
disorder measured by the Diagnostic Interview Schedule and 1.9% when
measured by the South Oaks Gambling Screen and an additional 2.8%-7.5% had
problem gambling (11). The National Epidemiologic Survey on Alcohol and
Related Conditions (NESARC), however, found that only 0.4% of adults in a
community sample met current criteria for gambling disorder (12). A meta-
analysis of 120 prevalence estimate surveys completed in North America from
the late 1970s to the late 1990s found that the lifetime estimate of gambling
disorder was 1.6% and of problem gambling was 3.9%, for a combined rate of
5.5% for some kind of disordered gambling (13); however, gambling exposure
may influence prevalence rates of gambling disorder (14).
Subpopulations, including military veterans, young adults, and adolescents,
have also demonstrated remarkable rates of problem gambling or gambling
disorder. A recent study of 3157 US veterans noted that 2.2% met criteria for at-
risk or problem gambling (15). Young adult (18-22 years) and adolescent (14-18
years) studies have also illustrated that problem gambling is relatively common.
An anonymous survey study of 791 college students (16) found gambling
disorder prevalence of 0.6%, while a recent study of 1313 adolescents showed
problem gambling rates of 1.2% and at-risk gambling rates of 4% (17). In a
global public health concern, similar rates of gambling disorder have been
reported in the general population and subgroups of the general population of
other countries (18–22).
The incidence of gambling disorder appears higher in clinical samples. In
individuals seeking treatment for substance use disorders, lifetime estimates of
gambling disorder range from 5% to 33% (23–25). In studies of psychiatric
inpatients, estimates of lifetime gambling disorder have ranged from 4.9% in
adolescents to 6.9% in adults (26–29).
There has been an accelerated proliferation of gambling venues since 2000,
particularly with online gaming, Native American casinos, and state-legalized
forms of gambling such as riverboat gambling and casinos (30,31). With
increased opportunity to gamble, some research suggests that we can expect
greater rates of gambling disorder in the future (13,32,33). Physicians, therefore,
will likely be seeing more individuals struggling with gambling disorder and
need to be skilled in assessing and treating this disorder.
ASSESSMENT
Gambling behavior and expenditures can be reliably measured with a timeline
follow-back interview adapted from a method used for individuals who have
problems with alcohol. There are also multiple measures to examine severity of
urges to gamble, such as the clinician-administered Yale-Brown Obsessive
Compulsive Scale Modified for Pathological Gambling or the self-report
Gambling Symptom Assessment Scale, both of which assess gambling urges and
behavior and have demonstrated excellent reliability and validity.
A range of self-report and interview-based measures to screen for a gambling
disorder have been developed. The most well-known screening instrument is the
South Oaks Gambling Screen (SOGS), which was based on DSM-III criteria
(30). Other screens include the Problem Gambling Severity Index and the
National Opinion Research Center DSM-IV Screen for Gambling Problems
(NODS) (30).
Clinical Characteristics
Gambling disorder often begins in adolescence or early adulthood, with males
tending to start at earlier ages (12,34,35). Although prospective studies are
largely lacking, gambling disorder appears to follow a trajectory similar to that
of substance use disorder, with high rates in adolescent and young adult groups,
lower rates in older adults, and periods of abstinence and relapse (36). Gambling
disorder can be a serious psychiatric disorder, but there is recent evidence that
approximately one-third of individuals with gambling disorder experience
natural recovery (ie, without formal treatment or attendance at Gamblers
Anonymous) (37). The research on natural recovery, however, is based on
retrospective reports, and there is no data regarding whether these individuals
who are symptom-free for 1 year remain free of symptoms beyond that time or
whether they relapse or change addiction.
Significant clinical differences have been observed in men and women with
gambling disorder (38,39). Men with gambling disorder are more likely to be
single and living alone as compared to women with the disorder (40). Males with
gambling disorder are also more likely to have sought treatment for DSM-IV–
defined substance abuse (41), have higher rates of antisocial personality traits
(34), and have marital consequences related to their gambling (34). Though men
seem to start gambling at earlier ages and have higher rates of gambling disorder,
women, who constitute ~32% of those with gambling disorder in the United
States, seem to progress more quickly to severe consequences than do men
(42–44). But, women with gambling disorder are more likely to recover from
and to seek treatment for their gambling problem (45).
The types of gambling preferred by men tend to be different from those
preferred by women. Men with gambling disorder have higher rates of
“strategic” forms of gambling, including sports betting, video poker, and
blackjack. Women, on the other hand, have higher rates of “nonstrategic”
gambling, such as slot machines or bingo (43,46). In regard to gambling triggers,
though both men and women report that advertisements trigger their urges to
gamble, men tend to report gambling for reasons unrelated to their emotional
state, whereas women report gambling to escape from stress or owing to
depressive states (35,41,43,46,47). Higher rates of sensation-seeking or “action”-
seeking behavior in men have been suggested as the possible reason for this
difference in gambling preference (43,48,49).
Functional Impairment, Quality of Life, and

Legal Difficulties
Individuals with gambling disorder suffer significant impairment in their ability
to function socially and occupationally. Many individuals report intrusive
thoughts and urges related to gambling that interfere with their ability to
concentrate at home and work (47). Work-related problems such as absenteeism,
poor performance, and job loss are common (42). The inability to control
behavior about which a person has mixed feelings may lead to feelings of shame
and guilt (47). Gambling disorder is also frequently associated with marital
problems (47) and diminished intimacy and trust within the family (50).
Financial difficulties (44% of those with gambling disorder report loss of savings
or retirement funds, and 22% report losing homes or automobiles or pawning
valuables owing to gambling) often exacerbate personal and family problems
(47).
With the functional impairment that these individuals experience, it is not
surprising that they also report poor quality of life. In three studies
systematically evaluating quality of life, individuals with gambling disorder
reported significantly poorer life satisfaction compared to general, nonclinical
adult samples (51–53).
Gambling disorder is also associated with greater medical comorbidity (eg,
cardiac problems, liver disease, obesity) and increased use of medical services
(54–59). Possible reasons for the association of gambling disorder with health
problems might be the sedentary nature of gambling, reduced leisure and
exercise time, reduced sleep (60), increased stress, and increased nicotine and
alcohol consumption (11).
Many individuals with gambling disorder report the need for psychiatric
hospitalization owing to the depression, and at times suicidality they feel was
brought on by their gambling losses (46). Research on individuals in gambling
treatment centers has found that 48% of individuals report having had gambling-
related suicidal ideation at some time (61). The often overwhelming financial
consequences, such as bankruptcy (62), associated with gambling disorder may
also contribute to attempted or completed suicide. A study of Gamblers
Anonymous participants (recruited through a gambling telephone hotline) found
that 17%-24% reported having attempted suicide owing to gambling (63).
In addition to the emotional impact of problem and gambling disorder, many
individuals with gambling disorder have faced legal difficulties related to their
gambling. One study found that 27.3% of DSM-IV–defined pathological
gamblers had committed at least one gambling-related illegal act (64). Problem
or gambling disorder may lead people to engage in illegal behavior including
embezzlement, stealing, and writing bad checks in order to either finance the
gambling behavior or to compensate for past losses related to the excessive
gambling (63). Another study found high percentages of pathological gamblers
endorsing prior acts of embezzlement (31%) and robbery (14%) (65).
Although gambling disorder is associated with multiple legal and functional
difficulties, one caveat is that the research is based on relatively small numbers
of individuals seeking treatment for gambling disorder, and, therefore, these
studies may reflect the more severe cases of gambling disorder.
Psychiatric comorbidity is common in individuals with gambling disorder (66).
Frequent co-occurrence has been reported between substance use disorders
(including nicotine use disorder) and gambling disorder, with the highest odds
ratios generally observed between gambling and alcohol use disorders
(10,67–69). A Canadian epidemiological survey estimated that the relative risk
for an alcohol use disorder is increased 3.8-fold when disordered gambling is
present (70).
Among clinical samples, 52% of Gamblers Anonymous participants reported
either alcohol or drug use (71), and 35%-63% of individuals seeking treatment
for gambling disorder also screened positive for a lifetime substance use disorder
(1), rates notably higher than that found in the general population (26.6%) (72).
Similarly, a recent study of 84 treatment seeking individuals with gambling
disorder noted lifetime rates of attention deficit hyperactivity disorder (ADHD)
in 26.3% of the sample, much higher than the general population rates of 4%-5%
(73).
Other studies clinically assessing co-occurring disorders in treatment-
seeking individuals with gambling disorder have also noted high estimates of
mood disorders (34%-78%) (47,74–76). In 1984, McCormick et al. (74) studied
38 cases of treatment-seeking gambling disorder patients with major depressive
disorder and found that, in 86% of cases, the gambling problem preceded the
onset of depression. These findings, however, need to be interpreted with caution
because the majority of these studies were derived from treatment-seeking
pathological gamblers, which may or may not reflect non–treatment-seeking
gambling disorder individuals. Yet, they also raise the question of whether co-
occurring mood disorders may be secondary to gambling disorder. A twin study
of self-reported family history to estimate shared genetic contributes to gambling
disorder and major depression in men (77), however, suggests a possible shared
biological predisposition to the co-occurrence of the disorders.
High prevalence estimates of co-occurring anxiety disorders (28%-40%) also
exist in those with gambling disorder (72,78,79), but not all anxiety disorders are
seen with equal frequency (80). Research suggests that estimates of co-occurring
generalized anxiety disorder range as high as 40% among gambling disorder
patients (67), whereas those of obsessive–compulsive disorder may be as low as
1% (1). The relationship of obsessive–compulsive disorder to gambling disorder,
however, has produced a mixed picture, with some studies reporting high
estimates (17%-20%) (70,71) and other investigations generating low estimates
(1%) (67). The rates of co-occurring disorders often have wide ranges, and this
may be owing to lack of structured clinical interviews used in assessing
comorbidity, the small sample sizes of gamblers assessed, the sample selection,
and the possible heterogeneity of gambling disorder.
Significantly, fewer data are available regarding the frequencies of Axis II
personality disorders in pathological gamblers. Studies have shown that
estimates of any personality disorder in those with gambling disorder range from
25% to 93% (75,80–82). Borderline (3%-70%), narcissistic (5%-57%), avoidant
(5%-50%), and obsessive–compulsive (5%-59%) personality disorders are most
commonly reported (75,81,82). One of the best-studied personality disorders in
gambling disorder, antisocial personality disorder, has been found in 15%-40%
of gambling disorder patients, a frequency higher than the 0.6%-3% estimates
reported for the general population (83,84). Although multiple reasons may
explain the elevated rates of comorbid antisocial personality disorder in
gambling disorder, evidence from past studies suggests a possible shared genetic
vulnerability between gambling disorder and antisocial personality disorder (85).
Family History
High frequencies of psychiatric disorders are seen in the first-degree relatives of
those with gambling disorder. Commonly reported conditions include mood,
anxiety, substance use, and antisocial personality disorders (51,85,86). In two
studies of first-degree relatives of those with gambling disorder, 17%-33% had a
mood disorder, and 18%-24% reported an alcohol use disorder (71,86). In
another study of 51 gambling disorder patients, 50% had a parent with an
alcohol use disorder (87). A large sample of 517 pathological gamblers found
that subjects with at least one problem gambling parent were significantly more
likely to have a father with an alcohol use disorder, report daily nicotine use, and
have significantly worse legal and financial problems compared to the cohort
without a problem gambling parent (88).
Studies have also found that 20% of the first-degree relatives of pathological
gamblers also have gambling disorder (89). Recent research examining possible
familial aggregation of gambling disorder found that individuals with a problem
gambling parent were at a 3.3 times higher risk of being a gambling disorder
(90). Similarly, Gambino et al. (91) found that problem gamblers at a Veterans
Health Administration hospital were up to eight times more likely to have a
parent with a gambling problem than were nonproblem gamblers. In one of the
few studies to use a psychometrically sound instrument (Family History
Research Diagnostic Criteria) to collect family history data, the researchers
found that 31% of first-degree relatives of gambling disorder patients had a
lifetime alcohol use disorder and 19% had lifetime major depressive disorder
(51).
In one of the few studies to use a control group to examine familial
aggregation of psychiatric disorders among those with gambling disorder, Black
et al. (92) examined 31 gambling disorder probands and 31 control probands.
Lifetime estimates of gambling disorder were significantly higher in family
members of pathological gamblers (8.3%) compared to control subjects (2.1%)
(odds ratio, 4.49; p = 0.018). Similarly, elevated estimates were observed for
substance use disorders (odds ratio, 4.21) and antisocial personality disorder
(odds ratio, 7.73) (92).
TREATMENT
Psychologically Based Treatments

Although there is a long literature of case reports using psychodynamic
psychotherapy and psychodynamic psychotherapy is often incorporated into
multimodal, eclectic, and integrated approaches to gambling disorder, there are
no randomized controlled trials supporting its use (93). Similarly, although some
evidence exists that Gamblers Anonymous (94–97) and self-exclusion contracts
(98–101) may be beneficial for pathological gamblers, limited and conflicting
data assessing the long-term efficacy for these interventions have been
published.
A variety of psychosocial treatments have been examined in controlled
studies for the treatment of gambling disorder (102). Cognitive strategies have
traditionally included cognitive restructuring, psychoeducation, and irrational
cognition awareness training. Behavioral approaches focus on developing
alternate activities to compete with reinforcers specific to gambling disorder as
well as the identification of gambling triggers (see Table 45-1 for a summary of
psychotherapeutic treatments). Although no data support its use for gambling
disorder, contingency management has been used successfully in the treatment
of individuals with substance use disorder who also gamble and has not
worsened the gambling behavior in these individuals.
Table 45-1 Controlled Psychological Treatment Trials

Assessment of Psychologically Based
Treatments
Empirical studies of CBT and using various elements CBT (ie, cognitive or
behavioral therapy, motivational interviewing, and CBT workbooks) support the
efficacy of using CBT for those with gambling disorder, because the majority of
trials found reductions in gambling disorder symptomatology compared to the
control conditions. However, these trials are insufficient to provide information
about the optimal treatment duration and the level of training needed by the
therapy administrator. Both brief and longer treatments have been found
effective, but no study has randomized subjects into psychotherapeutic
treatments of varying durations to determine the most efficacious treatment
length. In addition, few studies have long-term follow-up, highlighting the need
for future studies to include long-term follow-up visits to assess maintenance of
therapeutic gains.
Furthermore, few studies provided a detailed description of the content of
the therapy sessions or workbook and measurements of therapist adherence and
competence. Inclusion of these items would aid in the interpretation, and
application of study findings, for lack of therapist adherence to study protocol,
may confound study results. Characteristics of individuals with gambling
disorder who succeed in and do not respond to psychotherapy also need to be
investigated. Possible variables that impact individual success as well as
treatment adherence may include insight, desire to change, comorbid
psychological and physical conditions, and impulsivity.
Pharmacotherapy
No medication is currently approved by the U.S. Food and Drug Administration
and indicated for the treatment of gambling disorder. Twenty randomized,
placebo-controlled trials of pharmacotherapy treatment in gambling disorder
have been conducted, and these studies suggest that medications may be
beneficial in treating gambling disorder (see Table 45-2 for a summary of
pharmacotherapeutic treatments).
Table 45-2 Controlled Pharmacotherapeutic Treatment

Trials
Assessment of Pharmacotherapy
Due to the promising results of the double-blind trials of naltrexone and
nalmefene, opioid antagonists appear to be the most promising pharmacological
treatments for gambling disorder. Similar to the nalmefene, however, empiric
trails of naltrexone should be conducted at additional research sites to examine
the efficacy of naltrexone in varying patient populations. Results from trials
investigating the glutamate modulator, N-acetylcysteine, and lithium suggest that
these medications may also be effective, but with only one trial completed for
lithium and two for N-acetylcysteine, additional research is needed to bolster
support. Antidepressants have been the most widely examined ones with
findings providing indefinite results, yet for individuals with high anxiety,
escitalopram may be an effective treatment. Currently, no evidence supports the
use of atypical antipsychotics.
More research is needed to determine the most effective dosage of each
medication. Currently, only two studies (131,133) assessed the differential
impact of various dosages. Also unevaluated is the long-term impact of these
medications, with only two studies (135,137) assessing the pharmacological
treatment effect for longer than 6 months. One challenge in pursuing these data
is that studies historically have higher dropout rates (44%-59%) (135,137).
Understanding clinical and demographic variables may also help clinicians
find the most efficacious treatments. Individuals with intense gambling urges
may respond better to naltrexone (131), and males and younger individuals with
gambling disorder may respond well to fluvoxamine (137). There are limited
data concerning the efficacy of pharmacotherapy for individuals with gambling
disorder and a comorbid psychiatric disorder. Preliminary findings suggest that
individuals with gambling disorder and bipolar disorder may respond best to
lithium (144), while those with comorbid anxiety may find relief with
escitalopram (140). These findings suggest that investigating the clinical
characteristics of individuals who positively respond (as well as those who do
not respond) to treatment is necessary. In addition, no randomized, placebo-
controlled studies have been completed comparing pharmacotherapy treatments
or comparing pharmacotherapy to psychotherapy. These trials would provide
insight into which individuals may respond best to a certain class of medication
or psychotherapeutic treatment.
Treatment Recommendations
Gambling disorder is a common, disabling psychiatric disorder that is associated
with high rates of co-occurring disorders, particularly substance use disorders,
and high rates of illegal activities. Psychotherapy and pharmacotherapy have
shown a promise in the treatment of gambling disorder. Based on the treatment
literature, the off-label trials of naltrexone would appear the most promising
pharmacological option for a working clinician. A selective serotonin reuptake
inhibitor antidepressant used off-label may also be beneficial particularly when
the individual has comorbid depression or anxiety.
In terms of psychosocial treatments, cognitive–behavioral therapy appears
promising. There are several manualized forms of this therapy (2,147–149).
Although the stronger evidence suggests that eight sessions of CBT should be
considered, some data suggest that even fewer sessions or brief interventions
may be effective. With a manualized treatment, counselors with a background in
addiction counseling should be able to deliver the treatment with minimal
training.
Even knowing the evidence for various treatment options for gambling
disorder, other factors may influence in which treatment option is chosen for a
particular patient. First, many clinicians are simply unaware of gambling
disorder. Therefore, if a clinician is referring a patient for either medication
management or psychotherapy, it may simply be difficult to find people who
know how to treat the behavior. This problem can be minimized by having a list
of providers who know about gambling disorder and can provide treatment. For
example, if no one is available to do CBT for gambling disorder, then perhaps
medication management should be attempted first.
Second, there are no clear recommendations of treatment for the clinician to
follow. For example, it is unclear exactly how many sessions of CBT are most
helpful for gambling disorder. The exact dose of medication or duration of
medication trial for optimal treatment is also unknown. These gaps in knowledge
make it difficult to inform patients about what their care may entail and what
expectations they may have.
Third, individuals with gambling disorder exhibit high rates of placebo
response in treatment studies. Clinicians need to understand that for many
patients with gambling disorder, simply talking about their problem will help
substantially at first. This initial robust response, however, may cause the
clinician to believe that his or her treatment approach is successful. Clinicians
should carefully monitor the patient for several months and not assume they will
continue to do well. Also, involving a family member or close friend in
treatment efforts who can assist the patient in monitoring their behavior and
provide accountability may be beneficial for some patients.
Fourth, impulsive patients do not often follow recommendations or follow-
up with treatment. The treatment data consistently show that dropout rates are
high for gambling disorder. This may be owing to two factors: first, patients
often believe they are doing better than in fact they are and therefore see
treatment as unnecessary, and, second, they do not have an instantaneous
response and therefore do not stay with treatment. Both of these concerns can be
minimized by providing psychoeducation about the illness, detailing the
expectations of treatment, and expressing the need to stay in treatment.
ACKNOWLEDGMENTS
This research was supported in part by the Center for Excellence in Gambling
Research grant by the National Center for Responsible Gaming (NCRG).
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CHAPTER 46
Problematic Sexual Behaviors and
“Sexual Addiction”
Timothy M. Hall, Simone H. Schriger and Steven
Shoptaw
CHAPTER OUTLINE
Historical, Legal, and Cultural Contexts
High-Volume Sexual Behaviors: Hypersexual Disorder and Sexual
Addiction
Paraphilias and Paraphilic Disorders
Pedophilia and Sex With Minors
Compulsive Sex in Combination With Substance Use
Assessment and Treatment of Problematic Sexual Behaviors
Pharmacotherapy Strategies
Summary
A number of types of sexual behavior that are perceived as compulsive and that
are distressing to the patient, their partners, or other persons, may come to
clinical attention at the initiative of the individual or their partner or through
involvement in the legal system. These include paraphilias and paraphilic
disorders, concerns for excessive sexual desires and behaviors (high numbers of
partners, excessive masturbation, compulsive pornography consumption, etc.),
and the combination of compulsive sexual behavior with the use of psychoactive
drugs (colloquially known as “chemsex”or “partying”).
All of these have been grouped by some clinicians and researchers under
labels such as “sexual addiction” and related constructs. However, significant
challenges arise in extending the conceptual frame of addiction and addiction
treatment to behavioral problems that do not involve substance use. On the one
hand, The Diagnostic and Statistical Manual of Mental Disorders, 5th edition
(DSM-5) includes Gambling Disorder as a diagnosis. On the other, proposals for
two constructs related to compulsive sexual behaviors, sexual addiction and
hypersexual disorder, were rejected for lack of empirical support and lack of
consensus among researchers and clinicians. Much of the research on these and
related constructs has been limited by small sample sizes, lack of replication, and
arbitrary definitions—such as deciding that seven or more orgasms per week
after the age of 15 represents pathology (1). As we discuss below, competing
theoretical constructs and terminology further complicate discussion of
problematic sexual behavior (PSB).
In addressing the concerns of patients who report distress over their sexual
behaviors or fantasies, we caution clinicians to conduct a careful
biopsychosocial assessment to understand both the specific content of their
sexual fantasies and behavior (which may suggest a specific paraphilic disorder
or specific internal conflicts), and the personal history and social context in
which they are occurring. Such patients tend to be quite heterogeneous (2).
Labeling patients with sexual addiction or hypersexual disorder risks
medicalizing problems in their primary relationships or exacerbating negative
cultural or individual attitudes toward sexuality; these negative attitudes have
been found to predict self-diagnosis of sexual addiction better than do objective
behavioral measures of sexual frequency or of specific behaviors or fantasies
(3,4). It may also distract from identifying and treating primary mood,
personality, substance use, or obsessive–compulsive disorders that have co-
occurring features involving PSBs, or a specific sexual disorder such as a
paraphilic disorder (2) which all have greater evidence bases for diagnosis and
treatment.
This chapter will use problematic sexual behavior as a more theory-neutral
term that is closer to the clinical phenomenology. “Problematic” here is
deliberately broad: patients may present because of ego-dystonic distress over
the content or frequency of their fantasies or behaviors, or because their partner
or family members are distressed by them, or because their behaviors have
incurred legal or other disciplinary sanctions (such as violating workplace rules).
In the following, we describe some of the historical context for diagnostic
categories related to PSB broadly, as well as some of the different clinical and
forensic traditions that have investigated and theorized PSB. The remainder of
this chapter then discusses three broad areas of PSB that have sometimes been
grouped together with the concept of sexual addiction.
The closest constructs to sexual addiction are those characterized by high-
volume sexual behaviors (HVSB) generally: high numbers of partners, high
frequency of partnered sex or masturbation, or high use of pornography. We will
refer to these collectively as HVSB, and will use specific terms like sexual
addiction, hypersexual disorder, or compulsive sexual behavior when referring to
individual studies or theories that use these particular constructs.
The second set of PSB includes the paraphilias, defined as intense sexual
arousal to atypical sexual objects, situations, fantasies, or persons. There is great
difficulty in objectively determining what counts as atypical. In practice, those
paraphilias that come to clinical attention are often strong attractions to sexual
objects or partners and situations other than consensual sexual behavior with an
adult partner. When paraphilias cause ongoing emotional distress or illegal or
harmful behavior, they may rise to the level of paraphilic disorders.
Thirdly, we will consider the problem of compulsive sex co-occurring with
use of various drugs, particularly stimulants like methamphetamine or cocaine
and also club drugs such as 3,4-methylenedioxymethamphetamine (MDMA) and
gamma-hydroxybutyric acid (GHB). Known in the United States since at least
the 1990s as partying or PnP (for “party and play”), and increasingly denoted by
the British slang term chemsex, this is more common among men who have sex
with men (MSM), though it occurs in other populations. This mixture of sex and
drugs is a classical addiction embedded in a powerfully reinforcing sexual and
cultural matrix, which greatly complicates standard approaches to addiction
treatment (5). For each of these sets of conditions, we review some of the
relevant literature on prevalence, etiology, and comorbidities.
Finally, we review guidelines for treatment, necessarily based on a
combination of general good clinical practice for behavioral disorders and a
limited evidence base for PSB. Of the subtypes of PSB, treatments for paraphilic
disorders have been best studied, especially libido-suppressing pharmacological
treatments for pedophilic disorder and other paraphilic disorders involving
compulsions toward sexual assault. Aspects of these treatments may be
considered for other PSB conditions presenting serious risk of injury, legal
consequences, or psychological distress.
HISTORICAL, LEGAL, AND CULTURAL

CONTEXTS
In spite of definitional problems, “deviant” and compulsive sexual behaviors
have been a focus of clinical attention since the early days of the modern
medical and mental health professions (6), along with speculation about their
etiology (7) and attempts to change the sexual drives or behaviors. We mention
this history to underscore the ways in which historical and cultural contexts
shape the perspectives of professionals regarding sexual behaviors and whether
they require clinical attention. We also note that in different eras, a particular
behavior may be seen as a legal issue, a moral issue, a medical issue, or as
unproblematic variation (8). At various times, the following have all been seen
as deviant forms of sexual behavior and subject to medical attention: sexual
attraction to adults of the same sex, masturbation (under the term onanism), (9)
conceiving a child outside of marriage, (10) “feminine” behavior in a man, (11)
and even the expression of sexual desire in a woman (12). These are no longer
regarded as abnormal by most medical and mental health professionals. In
studying these phenomena, researchers have been more successful at
documenting the wide variety of human sexual behavior and desire than in
proving hypotheses about etiology. Attempts to develop cures for sexual
behaviors, drives, and orientations that are seen as problematic, whether by
society at large or by the individual in question, have been even less successful.
Assessing problematic and merely variant sexual behavior entails
distinguishing among sexual desires or orientations (some of which may be
considered paraphilias), sexual behaviors (that may or may not be motivated by
a strong orientation toward a particular kind of sexual partner or sexual act), and
context (a particular behavior may be problematic in one location or
circumstance and not another). For instance, consensual sex between a 17-year-
old and a 15-year-old may be legal in one state but count as statutory rape in
another. A man who is highly aroused by women’s feet and footwear may be
happy in a relationship with a woman who finds foot massages enjoyable, may
be unhappy in a relationship with a woman who finds his attraction strange or
disgusting, and may come to legal or clinical attention if he attempts to satisfy
his sexual desires by groping a woman’s feet without her permission. It is also
necessary to bear in mind that random instances of behavior do not by
themselves meet criteria for a disorder. For example, a nonconsensual sexual
grope may legally count as assault depending on the circumstances, but it is not
equivalent to a diagnosis of frotteuristic disorder if it occurs in the absence of
persistent fantasies and compelling urges about sexual groping.
Boundaries that define pathological (or illegal) sexual behavior are easiest to
specify when they involve children or nonconsensual aggression. Indeed, serious
legal sanctions are imposed on adults who express sexual urges or fantasies
involving children (child sexual abuse, child pornography) or nonconsenting
adults (domestic violence/rape). Strict mandated reporting laws require
clinicians to inform local authorities of domestic violence or rape, suspected
child sexual abuse, or sometimes even significant potential risk for child sexual
abuse. Clinicians should know and comply with their state and local legal
requirements for reporting these behaviors.
Several clinical and intellectual traditions have attempted to demarcate,
explain, and treat PSB. A tradition in general and forensic psychiatry has drawn
on biomedical models, emphasized legal and social aspects, and emphasized
taxonomic over dimensional concepts. Psychoanalytic traditions have more often
assumed a dimensional or dynamic model of PSBs and desires, with an emphasis
on clinically significant distress and a range of putative etiologies (7).
The scientific study of human sexual behavior, sexology, has a rich tradition
of its own, which intersects with aspects of clinical and developmental
psychology (13), embryology, endocrinology and behavioral neurobiology
(14,15), sociology (16,17), and other fields. In the United States and Canada,
sexology has tended to be an academic rather than a clinical discipline, which
may partly explain why North American clinicians are often less familiar with
sexological approaches than with traditions that are more based in clinical
disciplines. More recently, concepts from addiction have been applied to PSBs
and desires, employing terms like sexual addiction (18), compulsive sexual
behavior (19), and hypersexual disorder (1).
HIGH-VOLUME SEXUAL BEHAVIORS:

HYPERSEXUAL DISORDER AND
SEXUAL ADDICTION
Several competing sets of diagnostic criteria have been proposed to describe
pathological HVSB, reflecting different theoretical concepts (see Table 46-1).
Hypersexual disorder describes a condition of recurrent and intense sexual
fantasies and behaviors that cause distress, are inappropriately used to cope with
stressful events or dysphoric emotional states, cannot be voluntarily curtailed,
and risk or cause harm to oneself or others; this is seen as potentially related to
impulse-control disorders (20). At least two different versions of sexual
addiction have been proposed, modeled after criteria sets for substance use
disorders, and operationalizing analogues of tolerance (needing increased
amount or intensity of stimulation over time for the same effect) and withdrawal
(22,23). Several authors have also proposed alternative formulations more
directly linking a subset of HVSB to obsessive–compulsive disorders or
impulse-control disorders, though with less explicit proposed diagnostic criteria
(24,25).
TABLE 46-1 Proposed Diagnostic Criteria for High-

Volume Sexual Behavior Disorders
For clinicians evaluating patients for HVSB and other nonparaphilic PSB, the
International Classification of Diseases, 10th edition (ICD-10) does contain a
code that can be used for HVSB: F52.8 “Other sexual dysfunction not due to a
substance or known physiological condition.” This successor diagnosis to
nymphomania and satyriasis appears to have been retained for historical reasons
and its future in ICD-11 is unclear at this time. Under DSM-5, clinicians may
also code PSB under diagnostic entities that either feature impaired impulse
control (eg, impulse-control disorders not otherwise specified) or as a variant of
the paraphilic disorders, depending on the clinical presentation.
What are the characteristics of patients presenting with HVSB? Typically,
they spend large amounts of time planning or engaging in sexual behaviors,
either alone or with partners. These behaviors include hours spent on the Internet
or dating apps seeking sexual connections, engaging in sex, attending strip clubs
or sex clubs, or masturbating to pornography. Individuals complain of sexual
behaviors experienced as repetitive, persistent, compulsive, and out-of-control.
When not engaged in the behaviors, individuals report obsessive thoughts about
sex.
HVSB shares some behavioral features with substance use disorders.
Individuals with HVSB repeatedly engage in sexual behaviors that they may
experience as compulsive, despite knowledge of adverse medical, legal, and/or
interpersonal consequences. Individuals spend large amounts of time planning,
engaging in, or recovering from the behavior. Some authors note the gradual
development of need for increased sexual activities to get the desired effects,
parallel to the concept of tolerance in persons with PSB, though this is largely
based on case reports. (In our literature review for this chapter, we were unable
to find documentation of tolerance in a rigorously defined study.) Others have
noted mood changes related to sexual activity (euphoria) or sexual abstinence
(depressed mood) (23). Finally, many who present with HVSB engage in sexual
behaviors to the neglect of social-recreational activities and role responsibilities
(18).
Negative self-evaluations are often part of the clinical picture, including
feeling abnormal or sick; feeling degraded, guilty, or ashamed; feeling regret,
depression, or discomfort; or feeling numb, hollow, or empty. Indeed, studies
have found that negative attitudes toward sexuality on the part of the person or
of his or her partner predict self-identification of sexual addiction better than do
objective measures of sexual acts, sexual partners, or time spent thinking about
sex (3,26). Similar findings held in multiple studies of self-identified
pornography addiction (4,27). These suggest that conflicts about sexual desires
and behaviors may be what lead a person or their partner to identify sexual
behavior as problematic, rather than an underlying physiological dysfunction or
simple frequency of sexual behaviors.
Psychometric analyses are vital to establishing construct validity of concepts
such as sexual addiction or hypersexual disorder. Recent analyses have assessed
the latent structure of criteria for hypersexuality (a set of measures of greater-
than-average sexual behavior that are related though not identical to proposed
criteria for hypersexual disorder), testing whether hypersexuality is a taxon
(present/absent) or dimensional construct. Dimensional structure implies a
continuous distribution whereas a taxon structure implies a categorical structure,
more consistent with the conceptualization of a mental disorder. In a general
population sample of 1108 male and 993 female Swedish adults, the analysis
favored a dimensional conceptualization of hypersexual behavior, particularly in
men though less clearly in women (28). The same report also analyzed responses
to hypersexuality questions with 716 male sex offenders, the vast majority of
whom (n = 709) were currently incarcerated for sexual crimes. Again, results
were consistent with a dimensional model of hypersexuality. Results of a recent
study of college students supported a dimensional model for both males and
females (29). Factor analyses of sexual behavior data gathered from the general
population suggest that excessive sexual behavior falls at the tail end of a
spectrum of sexual desire.
Problems in defining HVSB complicate estimating population prevalence.
Kafka proposed a statistical cutoff as a proxy to define hypersexuality–among
men–as persistence of seven or more orgasms per week for a minimum duration
of 6 months or more after age 15 (1). This characterizes between 3% and 15% of
responses in surveys of male sexual behavior in the United States (1). The initial
proposal for hypersexual disorder was based on studies of men with paraphilic
disorders or related conditions; some 72% of these met the threshold for
hypersexual desire as indicated by spending 1-2 hours per day engaged in their
compulsive sexual behaviors. (For comparison, American adults in 2016 spent 4-
5 hours per day watching television or nonpornographic video (30).)
Defining hypersexual disorder primarily in terms of frequency of orgasm
may be problematic because sexual behaviors may have very different
significance in different contexts. For example, among married persons, higher
frequency of sexual intercourse with their spouse has been associated with
greater reported happiness, while higher rates of masturbation correlated with
lower reported happiness (17). Clinical depression may result in depressed libido
and lower rates of all sexual activity, while conversely individuals may increase
masturbation or other sexual activity in order to modulate their mood (31). High
volumes of sexual activity may be a necessary but insufficient criterion for
defining proposed disorders like hypersexuality. Further research is needed that
takes into account context, meaning, and time course, in addition to frequencies
of sexual behaviors. Moreover, studies in men may not extend well to women,
who have been much less studied in regard to HVSB.
Etiology of HVSB
The quality of evidence supporting the etiology of HVSB is poor, relying heavily
on theoretical models rather than empirical data. There are no systematic studies
on the onset of such a disorder; however, self-reports of individuals seeking
treatment for HVSB suggest symptoms often started in their late teens or early
twenties and may be chronic or intermittent. From a developmental perspective,
human sexual behavior typically begins in early to mid-adolescence, with most
individuals initiating sexual behaviors by early adulthood. Acquisition of sexual
behavior during adolescence is marked by exploration and engaging in one or a
few episodes of uncommon sexual behaviors does not predict later sexual
problems. Repeatedly engaging in risky sexual behavior, combining alcohol or
substance use with sex during adolescence, or having multiple sexual partners
may signal increased risk for later problems; however, there are no indicators in
adolescence that reliably predict who will later develop HVSB.
There are better data documenting trauma in the histories of individuals,
especially women, who develop later HVSB. Traumatic experiences may include
childhood sexual abuse (18,32), early substance use, impulse inhibition
problems, and peer and family influences that predispose to HVSB from
modeling and neglect. In a retrospective survey on the sexual health of adults in
Sweden, both men and women who scored above 90% on measures consistent
with hypersexual behaviors (ie, times masturbated past month; times viewed
pornography past month; number sexual partners past year; more than one
current sexual partner; prefer casual sex; and had group sex) reported significant
correlations with separation from parents during childhood, earlier age of first
sexual experience, and more varied sexual behaviors while young (33). These
respondents reported significantly greater current rates of cigarette smoking,
being substantially drunk in the past month, ever having used illegal drugs, and
ever having gambled (33). There is a high co-occurrence of individuals with
HVSB and the experience of having family members with HVSB or addictive
disorders. HVSB may be related to a disposition to externalizing behaviors, and
potentially shared among antisocial behavior and substance use disorders (34).
Despite these associations, most youth who experience childhood sexual abuse,
early substance use, attention-deficit hyperactivity disorder (ADHD), and
impoverished social and family backgrounds do not develop HVSB.
Some instances of HVSB may represent an aspect of borderline personality
disorder or related disorders. Links between absence of fathers with earlier onset
of puberty, earlier sexual initiation, and higher numbers of sexual partners in
women have been noted by evolutionary psychologists as a possible
behavioral/learned response to unstable early social environments (35,36).
A few investigations have considered genetic contributions to the number of
sexual partners. Variation in the gene coding for the dopamine transporter, which
impacts synaptic levels of dopamine, was associated with the number of sexual
partners among men, but not among women (37). Several studies also have
found significant associations between genes regulating dopamine expression
and sexual behaviors (mostly numbers of sexual partners), though with no
consistent pattern of findings. Links between dopamine availability and sexual
behaviors are plausible, but genetic factors cannot yet reliably predict or explain
HVSB (38).
While this field struggles with consensus in definitions of disorder and of
etiology, we expect that findings for HVSB will parallel those for substance use
disorders, where the impact of individual genetic variations is minimal, genetic
and environmental factors interact in complex ways, and the genetic factors
identified will predispose the individual broadly to addictive behaviors or
problems with impulse control, rather than exclusively to HVSB. More research,
with consensus diagnostic criteria, and particularly in nonforensic and
nonparaphilic populations, needs to be done to better elucidate the etiology,
prevalence, and construct validity of HVSB.
Neurobiology of HVSB
There exists a small literature on neurobiology relevant to HVSB, primarily
among healthy males. Imaging studies have experimentally manipulated
presentation of erotic and neutral stimuli among young adult male heterosexual
subjects under positron emission tomography (PET) or functional magnetic
resonance imaging (fMRI) (39–41). Erotic visual stimuli activate brain regions
that include the right insula and claustrum (somatosensory processing and penile
erection), the hypothalamus and striatum (areas of dopamine signaling), the
anterior cingulate gyrus (shifting attention, repetitive behavior, endocrine and
gonadal secretions), in addition to activation in the occipital cortex (visual
processing) (40,41). Oei et al. (42) probed the role of dopaminergic tone in
sexual response by randomizing healthy males to haloperidol, levodopa or
placebo. Levodopa enhanced activation in the nucleus accumbens and the dorsal
anterior cingulate when participants were exposed to subconscious sexual
stimuli, while haloperidol decreased activations in these areas.
A role for dopamine in normal and aberrant sexual behavior has been
suggested by high prevalence of impulse-control disorders emerging in response
to dopamine agonist treatment among patients with Parkinson’s disease (PD).
Among 300 patients with PD, 58 (19.3%) self-reported new-onset behavioral
compulsions. Of those, 25 (43.1%) reported sexual compulsivity, and the
remainder reported gambling compulsion. All those who developed sexual
compulsivity were male, and all were on stable dopamine agonist therapy (43).
Preexisting histories of an impulse-control disorder (eg, substance abuse)
increased the odds of developing HVSB under dopamine agonist treatment.
These findings are echoed by a more recent study systematically investigating
impulsive behavior in patients with PD on dopaminergic agents. Of those
receiving the target dose, 24% developed new pathological behaviors (44).
Some of the neuroadaptations seen in substance use disorders have been
reported in HVSB (45), although other studies have failed to find similarities
(46). Case reports of brain injuries leading to sexual compulsivity later in the
lifespan suggest possible neurobiological mechanisms. Patients with brain injury
in right temporal areas sometimes develop sexual compulsivity, consistent with
PET studies associating these areas with male heterosexual response (45,47).
The evidence thus far demonstrates that complex human sexual behaviors
involve multiple systems and have complex neuroanatomical pathways.
However, a target site or target chemical that might represent a biological
substrate for HVSB or clearly related conditions has yet to be identified.
Reports consistently implicate impulsivity, obsessions, and compulsivity as
central issues in HVSB. Many psychiatric disorders share one or more of these
features. Impulsivity is a core feature of ADHD, bipolar disorders, and substance
use disorders. In a study describing comorbid problems of 932 individuals who
rated highly on measures of sexual sensation seeking and sexual compulsivity
(19), 28% reported working compulsively, 26% reported spending compulsively,
38% reported disordered eating, and 42% reported substance use disorders. High
prevalence of psychiatric comorbidities is also observed in community samples
of individuals who defined their behavior as sexually compulsive. In one (N =
36), 39% met criteria for lifetime mood disorders, 50% for lifetime anxiety
disorders, and 64% for lifetime substance use disorders (48). In another (N = 24,
including two females), all subjects met lifetime criteria for some Axis I disorder
(mood disorders, 71%; anxiety disorders, 96%). Fully 88% met criteria for any
current Axis I disorder (mood disorders, 33%; anxiety disorders, 42%), with
29% and 71% who met criteria for any current and lifetime substance use
disorder, respectively, with the most frequent diagnosis involving alcohol (49).
Some data point in the other direction, finding that individuals with other
psychiatric disorders have elements of HVSB. In a study of psychiatric
inpatients, one-third had comorbid impulse-control disorders, with 4.4% of these
having current and 4.9% lifetime prevalence of comorbid compulsive sexual
behaviors (50).
Depression
Among individuals with DSM-IV-defined substance abuse and dependence,
there is a high rate of psychiatric comorbidities, particularly depression. As
noted, in small samples recruited from the community, symptoms of depressive
disorders correspond significantly with symptoms of sexual compulsivity (37).
In a report on 669 urban MSM, sexual compulsivity was associated with
depression symptoms when controlling for a range of demographic and risk
variables (51).
Anxiety
The prevalence of current and lifetime anxiety disorders is reported earlier.
Presence of anxiety symptoms appears to be somewhat higher in individuals
rated as having sexual addiction as compared to controls. In one study,
participants recruited from 12-step self-help venues were classified into three
groups based on their behavioral presentations: “sexual addiction” (n = 32),
pathologic gamblers (n = 38), and nonaddicted controls (52). Comparison of
scores for the Symptom Check List-90-R along depression, anxiety,
interpersonal sensitivity, and obsessive–compulsive subscales showed
significantly higher scores for individuals in the self-identified sexual addiction
group than for controls.
Attention Deficit Hyperactivity Disorder

Some retrospective reports suggest associations between attention deficit
hyperactivity disorder (ADHD) during childhood and presence of HVSB (53).
Seventy-two individuals seeking treatment for HVSB completed a variety of
scales to assess symptoms of sexual compulsivity; 34% scored in the range of
probable ADHD diagnosis. Although retrospective reports indicate significant
correlation of ADHD in samples of men with behaviors consistent with HVSB,
it is also possible that childhood ADHD is a correlate of sexual behaviors in
adult men who have been imprisoned. In a small imaging study, men rated as
sexually compulsive made significantly more errors than did control participants
in Go-No-Go procedure, a behavioral measure that identifies impairments of
inhibitory control (54).
Personality Disorders
One study found that 46% of a community-based sample of individuals
identifying as having HVSB met criteria for any personality disorder,
predominantly Cluster C disorders (49). In a study of 403 adolescents seen in
primary care settings, those rated as having three or more symptoms of Axis II
diagnoses reported higher numbers of sexual partners than did those with
symptoms of two or fewer Axis II diagnoses. The association was stronger in
females than in males (55).These findings underscore difficulties in separating
out HVSB as a primary diagnostic entity from personality disorders. Acting out
sexually is a criterion for borderline personality disorder, and may be seen in
other Cluster B personality disorders (56), while Cluster C personality disorders
may entail excessive self-criticism and guilt.
PARAPHILIAS AND PARAPHILIC

DISORDERS
Definitions and Diagnosis
A paraphilia is an attraction or arousal to atypical objects, persons, or situations.
At one time paraphilias included phenomena from cross-dressing and frequent
masturbation to foot fetishism and sexual masochism. In recent decades,
“atypical” sexual desires and behaviors are more often seen as lying on a
continuum from strong preferences for certain physical types of partners or
situations, through harmless “kinks” that persons may include in their sexual
fantasies and behaviors, to paraphilias more strictly defined. Problems in
drawing clear diagnostic lines among these phenomena include changing sexual
behaviors and attitudes in the general population; distinguishing between
behaviors that are inherently problematic versus those that incur social stigma;
and distinguishing behaviors that are harmful to oneself or others versus merely
atypical. Research indicates that merely desiring or occasionally engaging in
unconventional sexual behaviors such as consensual bondage and domination,
sexual sadism and masochism (BDSM) is relatively common (rates of sadistic
and masochistic behavior have been reported at 5.5% and 19.2%, respectively, in
a Canadian survey) (57) and is not necessarily associated with poorer mental
health or psychological maladjustment (58).
DSM-5 defines a paraphilia as “intense and persistent sexual interest other
than sexual interest in genital stimulation or preparatory fondling with
phenotypically normal, physically mature, consenting human partners.” (56)
Noting that “a paraphilia by itself does not necessary justify or require clinical
intervention,”DSM-5 further distinguishes a paraphilic disorder as “a paraphilia
that is currently causing distress or impairment to the individual or a paraphilia
whose satisfaction has entailed personal harm, or risk of harm, to others.” (56)
Eight specific paraphilic disorders are listed, (see Table 46-2), as well as a
category for other specific paraphilic disorder, which would include the many
historically named paraphilias, and unspecified paraphilic disorder, in situations
where there may be insufficient information to specify but there is evidence for
impairment. These specific paraphilic disorders are listed because they are
relatively common (compared to other paraphilic disorders), and satisfying them
is likely to entail harm or criminal activity. The sexual disorders section of ICD-
11 is likely to go even further in removing specific paraphilias from the list of
disorders, recognizing that “specific patterns of sexual arousal that are merely
relatively unusual, but are not associated with distress, dysfunction or harm to
the individual or to others, are not mental disorders.” (59)
TABLE 46-2 Specific Paraphilic Disorders Named in

DSM-5
Distinguishing paraphilias and paraphilic disorders from crimes of a sexual
nature has both clinical and legal ramifications. While some persons with
paraphilic disorders do commit sex crimes including rape, sexual assault of
adolescent minors, and child molestation, a majority of these crimes are
committed by persons who do not have a paraphilic disorder (60,61). There is a
contentious debate in many American and Canadian jurisdictions over
sentencing length and appropriateness of parole or probation for persons with
diagnosed paraphilic disorders who have been convicted of sex crimes. There is
a need to balance concerns for public safety—recognizing that their ongoing
strong desires for particular sexual acts may place them at higher risk of
recidivism—against obligations of fairness and justice (62,63). Conversely,
given that most crimes of sexual nature are not committed by persons with
paraphilic disorders, a focus on paraphilic disorders can be misleading both for
prevention and rehabilitation. Unfounded worries about generalized sexual
addiction also feed into public support for life-long registries of persons
convicted of sex crimes, which are largely unsupported by research findings and
can introduce unintended negative consequences to the individual and to the
community (64).
Etiology, Development, and Prevalence of

Paraphilic Disorders
Most paraphilias manifest during adolescence, though the individual may not act
on them or acknowledge them to other persons at that time. Several paraphilias
have been linked together in the courtship disorder hypothesis, which proposes
that voyeurism, exhibitionism, frotteurism (“mashing” or rubbing oneself against
another person, often in public), and telephone scatologia would all be
deviations from a psychological system whose normal function involves finding
and wooing a potential sexual partner (65). DSM-5 adopts the grouping of
paraphilias into two sets that are agnostic to etiology and development. Those
with anomalous activity preference focus on atypical behaviors: the courtship
disorders and the algolagnic, or pain-loving, disorders of sexual sadism and
sexual masochism. Paraphilic disorders with anomalous target preference, on the
other hand, are oriented toward targets other than adult humans; these include
pedophilic disorder, fetishistic disorder, and transvestic disorder (56).
It is difficult to ascertain prevalence of paraphilic disorders, as much of the
available data come from forensic or clinical samples that are not generalizable
to society at large. Additionally, many surveys ask about thoughts and fantasies,
which correlate weakly with behavior and are often mediated by other
personality factors such as antisocial traits or poor impulse control. For instance,
one study of male undergraduates (n = 103) found that 95% endorsed at least one
“deviant” sexual fantasy, and more than half the respondents in the same study
reported occasional, individual acts that might be considered deviant, such as
uninvited or nonconsensual sexual groping (44% of respondents, which counted
as a frotteuristic-type behavior). However, only a minority (38%) actually
carried out behavior from their specific sexual fantasies (66). Other studies have
corroborated this finding of relatively high rates of occasional fantasies along
paraphilic lines, but with much lower rates of acting them out, or of the
preoccupation and compulsiveness needed to meet diagnostic criteria for a
paraphilic disorder (67).
Prevalence data on the specific paraphilic disorders listed in the DSM-5 are
also highly variable across studies. Langstrom and Seto (68) found that in a
nonclinical, nationally representative sample of nearly 2500 Swedish adults,
11.5% of men and 3.9% of women reported at least one episode of voyeuristic
behavior. Other studies have reported rates of voyeuristic experience as high as
nearly 35%, noting voyeuristic behavior as one that often results in interaction
with law-enforcement, and the most common paraphilic disorder among men
(57). In the same Swedish sample, at least one instance of exhibitionistic
behavior was reported by 4.1% of men and 3.9% of women (68). However, Joyal
and colleagues (57) found that over 30% of their sample of over 1000 Canadians
had engaged in exhibitionistic behavior. Joyal et al. (57) found that fetishism was
the second most common paraphilic behavior, with 26.3% of their sample having
engaged in at least on fetishistic behavior in their lifetime. However, behavior
alone is not a formal disorder. For example, frotteuristic disorder rates are
difficult to classify accurately, as much of the data label any kind of groping or
nonpenetrative sexual assault as frotteurism, without evidence of whether
persons engaging in these behaviors also exhibit a compulsive element,
clinically significant distress, or impairment in functioning. A systematic review
found that estimated prevalence rates of frotteurism varied widely across studies,
ranging from 7.9% to 35% (69).
PEDOPHILIA AND SEX WITH MINORS

The paraphilias with the largest research database and that most often come to
legal attention are those that involve a predominant sexual attraction to children
or to adolescents. These should be distinguished from child molestation or child
sexual abuse, most instances of which are not committed by persons with a
predominant orientation toward minors. Additionally they should clinically be
distinguished from sexual acts between younger and slightly older adolescents or
young adults who may be just on the other side of the local age of consent.
Depending on the jurisdiction, these so-called “Romeo and Juliet” cases of
consensual sexual behavior between individuals a few years apart in age may be
legally prohibited, but they are often age-appropriate behavior rather than
evidence of a long-standing attraction to minors. For many paraphilia
researchers, pedophilia, strictly speaking, is a long-standing attraction to
prepubescent children, typically under the age of 11 or 12 or in Tanner stage 1.
Sex researchers distinguish this from hebephilia, attraction to pubescent
children, around ages 11-14, and ephebophilia, or attraction to older adolescents
in Tanner stages 3-4. These are research categories but not currently in DSM-5
or ICD-10 (70).
DSM-5 characterizes pedophilic disorder as a recurrent, intense attraction to
prepubescent children, generally under 13. The individual with pedophilic
disorder must be at least 16 and at least 5 years older than the child. DSM-5
further excludes “an individual in late adolescence in an ongoing sexual
relationship with a 12- or 13-year-old.” This does not speak to the
appropriateness or inappropriateness of such a relationship, but rather recognizes
that sexual exploration among adolescents does not reliably predict a lifelong,
persistent attraction to children as sexual objects.
DSM-5 characterizes pedophilic disorder not only by the nature of sexual
fantasizing (recurrent and intense) but also by interference in an individual’s life,
either by creating distress or interpersonal difficulty, or in the acting out on one’s
sexual urges. Much of the research on prevalence of pedophilic disorder focuses
on sexual fantasy and urges, not always distinguishing individuals who meet
DSM-5 criteria from those who do not. Additionally, many studies focus on
criminal or clinical populations, and thus may not be generalizable to the public.
These factors may contribute to overestimates of the prevalence of pedophilic
disorders.
There is wide consensus that prevalence of pedophilic disorder in the general
public is unknown due to lack of large-scale epidemiological surveys (71,72). In
studies examining sexual fantasy and urges, results indicate an upper limit of
around 5%, though the prevalence varies depending on the questions being asked
(56,71–73). Few studies have looked at sexual behavior involving children
among nonclinical samples. Dombert and colleagues found that prevalence
estimates for sexual behaviors involving children ranged from 0.04% to 5% (74),
and Mokros et al. estimate that lifetime prevalence of pedophilic disorder in
males is 0.5%-1% (75).
Etiology of pedophilic disorder and related disorders is not well understood.
Theories of developmental trauma or imprinting have been widely accepted, but
it remains that most survivors of child sexual abuse do not grow up to have an
attraction to children, and many persons with an attraction to minors were not
themselves sexually abused. However, there are suggestions of distinguishing
characteristics that identify men who develop pedophilic disorder. In one large
forensic study, diagnosis of ADHD and more than three head injuries
experienced prior to age 13 were associated with a preference for children as
erotic stimuli (76). In another study, men with pedophilic disorder (N = 65)
completed T1-weighted fMRI scans and voxel-based morphometry, which were
compared to 62 men who were nonsexual offenders. Findings showed significant
reductions in white matter volume in the fiber bundles of the superior fronto-
occipital fasciculus and the right arcuate in the pedophilia group. No such
associations were observed in scans from the 62 men who were nonsexual
offenders included as a control condition (47). These differences are observed in
fibers that connect areas of the brain that respond to sexual cues, suggesting that
pedophilia may result from disruption of the networks of brain regions
connected by these fibers. As noted, data were collected from a forensic setting
and may not represent men in the community with an attraction to minors who
do not act on those impulses (76). Antisocial traits have been found to predict
greater likelihood of acting on paraphilic impulses, and may also be a mediating
factor in paraphilic disorders involving sex with minors or nonconsenting
partners (57).
Treatment of pedophilic disorder is discussed together with treatment of
other PSB in the last section of this chapter.
COMPULSIVE SEX IN COMBINATION

WITH SUBSTANCE USE
Sex and substance use combine some of the most powerfully reinforcing and
potentially problematic behaviors known to humans. If we include alcohol in the
definition, the combination goes back for millennia, while sex in combination
with opioids or cannabinoids goes back at least centuries. Since about the 1970s,
however, we have seen a particular intersection of stimulants (cocaine and
methamphetamines), dissociatives (ketamine), and “entactogens” or
“empathogens” (MDMA, GHB, etc.) with sex, particularly among MSM, though
also in some other groups. This has been known in the United States under the
gay slang terms “partying,”“party and play,” or “PnP.”“Slamming” refers
specifically to injection drug use (IDU), although not only in the context of sex.
Like other instances of IDU, slamming carries elevated risks for transmission of
HIV, hepatitis B and C, and other blood-borne illnesses, as well as other risks
related to nonsterile needles. In the last few years, the British gay term
“chemsex” has gained increasing attention in the public health literature,
particularly in relation to prevention and treatment of HIV and STIs. On a public
health and sociological level, this intersection of sex, substance use, and risk for
HIV and STIs has been conceptualized as syndemic—that is, as mutually
reinforcing and complexly interacting epidemics, not merely as the problem of
an individual or as a single problem of a group (77).
CASE EXAMPLE
George is a 32-year old Caucasian-Filipino male who reports compulsive,
high-volume sexual behaviors linked to his use of methamphetamine. George
tells you that he has been “out” to his friends and family for about 9 years and
they are supportive of him being gay. George reported that during an episode in
San Francisco about 7-8 years ago, he was introduced to methamphetamine by
a sexual partner he met in a sex club. For a few years, George integrated
methamphetamine use with his sexual behaviors as it helped him to have a kind
of sex he couldn’t have when not under the influence, particularly being the
receptive partner in “bareback” (unprotected anal) group sex. George’s use of
methamphetamine and related sexual behaviors escalated to the point that he
couldn’t control his drug use, and about 5 years ago he lost his job. About the
same time, George became HIV positive. Since then, he has been adherent to
his HIV medicines, though his HIV physician has had to treat him for multiple
episodes of sexually transmitted infections (STIs), including syphilis. George
was first admitted to an inpatient program for methamphetamine use disorder 5
years ago, but he complained that no treatment programs have ever addressed
the sexual behaviors linked to his methamphetamine use. For the past 5 years,
George reports being hospitalized about once or twice per year, achieving
periods of 3-6 months of abstinence, followed by relapses and
rehospitalizations. Two years ago after a month of abstinence from
methamphetamine, George met online with a man who wanted to watch him
have sex with many unprotected partners. George bought a gram of crystal
methamphetamine, placed an Internet ad for men to have unprotected sex with
him in a hotel room, and had more than 60 sexual partners over a weekend
while the man watched from an adjoining room. George tells you this sexual
activity brings him great shame and has caused him physical harm
(hemorrhoid surgery 3 times) in addition to STIs. He has been unable to stop
the methamphetamine and associated sexual behaviors for longer than 2-3
months at a time (George does not engage in extreme sexual behaviors when
not under the influence). George denies any experiences of sexual molestation
or sexual abuse as a child, though he cannot remember his childhood in detail.
He volunteers that he has a fleeting memory of an older adult family member
making him have sex with family “friends” when he was around 10 years old,
but he’s not sure. He denies ever having sex with prepubescent boys and states
he has erotic feelings only for adult males. He is seeing you today as he wants
to get his life back. He asks whether he should return to an inpatient treatment
program for methamphetamine or to try outpatient approaches including 12-
step groups.
Prevalence data on compulsive sex in combination with substance use are

limited, in part due to the lack of a clear consensus on how to classify this
particular issue and whether it be viewed as primarily a poly-substance use
disorder, primarily a compulsive sexual behavior, or both. The British-based
“Chemsex Study” was one of the first quantitative publications on this topic. Of
more than 1100 respondents, around 20% reported engaging in compulsive sex
in combination with substance use within the past year, and 10% within the past
month (5). Another study found that in an MSM population in London, 99% of
individuals who used methamphetamine, 75% of those who used mephedrone,
and 85% of those who used GBL (a prodrug for GHB) reported using the drug
solely to facilitate sex, with 70% reporting having shared needles to inject drugs
(78). Though these numbers are concerning, it is impossible to extrapolate from
these to prevalence numbers for a potential disorder or persistent compulsive
behavior combining sex and drug use.
Compulsive sex in combination with substance use has been identified as a
growing public health issue and has been linked to high rates of HIV
transmission in many studies (79–81). In terms of treatment, programs such as
Dean Street Clinic in London are taking a pragmatic harm-reduction approach,
focusing on reducing the risk of transmission of HIV, hepatitis C, and other STIs.
The program provides education about needle sharing and mitigating risks of
overdose, aiming to build rapport with patients, which may ultimately result in
more comprehensive treatment. In their Lancet article, Kirby and colleagues
found that IDU among MSM involved in compulsive sex in combination with
substance use increased from 30% to 70% in a single year, with 70% of people
who injected drugs reporting needle sharing (82). The authors note that
individuals partaking in compulsive sex in combination with substance use often
maintain professional lives and thrive financially. Nonetheless, the health
consequences of compulsive sex in combination with substance use are
potentially serious, with a typical episode lasting up to 72 hours and involving an
average of five sexual partners. Kirby and colleagues report that 75% of those
using crystal methamphetamine, GBL, or mephrodrone are HIV positive, with
60% reportedly not taking antiretroviral treatment. Clinics serving lesbian, gay,
bisexual, and transgender (LGBT) clients report difficulty in meeting demand for
services related to compulsive sex in combination with substance use.
Special Populations: PSB Among MSM

We briefly address PSB among MSM in part because of the disproportionate
amount of research and clinical attention paid to this population. MSM have
been historically stigmatized, with their sexual behaviors often criminalized
and/or medicalized. In recent years, attention has focused on various constructs
of hypersexual behavior among MSM as putative mediating risk factors for HIV
and other STIs. Additionally, some MSM carry significantly negative and self-
critical attitudes toward their sexual desires and behaviors. Consequently, there
is a need to recognize potential risks among MSM presenting for concerns of
PSB. On the one hand, they may be at higher risk than some other persons with
PSB for contracting HIV or being introduced by sexual partners to HVSB in the
context of substance use. On the other hand, they may carry excessive shame
and guilt about their sexual orientation and same-sex experiences, with
potentially conflicting and exacerbating messages from their MSM peers, their
families and communities of origin, and their encounters with healthcare
providers; these may lead them to view relatively normal MSM experiences
through a lens of pathology, and may complicate efforts to access treatment for
PSB, substance use disorders, mental health services, or general healthcare.
Far less research has been addressed toward PSB among other sexual and
gender minorities, such as women who have sex with women, though many of
the same concerns about internalized stigma apply. Transgender women are
often included with MSM in studies of HVSB in context of substance use,
though there are a number of differences in their experience and social context.
There is a small and highly contentious literature on other PSB among
transgender persons, the nuances of which are beyond the scope of this chapter.
There is very little research on the sexual health needs of transgender men in
general. All of these topics need additional research to inform better clinical
care.
Studies indicate that a subgroup of MSM experience sexual behaviors that
are more compulsive and more distressing than for MSM in general. Use of
alcohol or drugs proximal to sex may loosen sexual safety protocols and lead to
unprotected sex, which carries increased risks for HIV infection among MSM.
As noted above, high volumes of sexual behavior do not necessarily constitute a
disorder. Among MSM who scored one standard deviation or higher above the
mean of the Sexual Compulsivity Scale (19), qualitative interviews indicated
five intrinsic explanations for sexually compulsive behaviors: negative affect,
low self-esteem, needs for validation and affection, stress release, and having a
high sex drive (83). Externalizing explanations included relationship issues, the
easy availability of gay sex, childhood sexual abuse, and parental
conflicts/deficiencies.
Correlates of scores of sexual compulsivity and health risk behaviors are
observed in several studies of MSM, particularly high numbers of sexual
partners and likelihood to engage in condomless anal sex. (84) Among HIV-
positive MSM in two studies, high scores on the Sexual Compulsivity Scale
corresponded with older age, using methamphetamine before or during sex,
going to sex venues or street corners for sex partners, low self-efficacy for
condom use, low levels of self-esteem, high disinhibition, and a high number of
HIV-negative or status-unknown sexual partners (51,85). These findings are
drawn from venue-based and convenience samples, which do not easily translate
into prevalence of PSB in the general population of MSM. Additionally, age
differences also correlate with different cultural cohorts or generations of MSM,
who may have very different experiences of and attitudes toward sexuality, drug
use, and HIV.
Though not specifically addressing PSB, there is a growing body of work
illustrating that reduction in drug use by providing evidence-based, cognitive
behavioral treatments for drug use disorders corresponds with reductions in
high-risk sexual behaviors. One example is Getting Off: A Behavioral Treatment
Intervention for Gay and Bisexual Methamphetamine Users, which adapts the
MATRIX Model manualized treatment for stimulant use disorders for gay- and
bisexual-identified clients. This approach facilitates clients undergoing intensive
outpatient treatment of their methamphetamine use disorder to enter a
conversation regarding the cultural, sexual, physical, and psychological aspects
of their sexual behavior. Outcomes from a randomized, controlled trial found
that among gay- and bisexual-identified clients with methamphetamine use
disorder, treatment-associated reductions in high-risk sexual behaviors are
observed up to 1 year after treatment entry (86), a finding that was replicated and
effectively implemented in a community setting (87). In a qualitative report on
the experiences of the men in the initial research project, participants noted the
primary mechanism driving reductions in their high-risk sexual behaviors, both
in numbers of partners and in episodes of condomless anal intercourse, was
treatment-associated reductions in methamphetamine use (88). The manual and
accompanying counselor training manual are available for download at
http://friendscommunitycenter.org/documents/Getting_Off_Treatment_Manual.pdf
It is difficult at present to know how best to characterize this intersection of
drug use and PSB, largely though not only among cisgender MSM, transgender
MSM, and transgender women. The particular role of methamphetamine in PSB
among MSM has been noted since the 1990s (89), and a focus of public health
discussion since the early 2000s (90). However, this needs to be considered in
the context of a long history of moral panics about drug use among MSM (91),
including earlier concerns about a possible causal role of nitrite poppers in
AIDS, which was later disproven (92). Additionally, use of alcohol and drugs in
relation to socializing and to sex has a complex history among LGBT
populations (93). The widespread availability of drugs in sexual contexts and
ongoing visibility of compulsive sex in combination with substance use also
complicate the recovery process from substance use disorders for many patients
from LGBT and other affected communities. Further research is needed to better
understand this intersection of sex and drugs in its social context and in relation
to behavioral health, in order to reduce further transmission of HIV and other
STIs.
ASSESSMENT AND TREATMENT OF

PROBLEMATIC SEXUAL BEHAVIORS
Assessment
Individuals who present for treatment or evaluation of PSB need careful
assessment to define the presenting problem. Standard areas to review include
current presentation and history of the PSB: Did something precipitate the visit?
Exactly what is the patient doing, at what frequency, and under what
circumstances to define compulsive sexual behaviors? What is the gender and
age of the partners involved with the individual? What is the development of the
behavior—from childhood to present? What is the individual’s experience with
sexual abuse, physical abuse, and head or other physical trauma as a child?
When were symptoms or distress the worst? What has helped reduce the severity
of symptoms or distress in the past?
As with substance use disorders, individuals presenting for treatment of PSB
may have limited motivation for treatment, particularly if referred by a partner or
mandated by a court. Thus, determining and enhancing motivation may be an
important element of treatment. After seeking a thorough understanding of the
chief complaint, it is important to establish whether or not there is victimization
in the history. Some forms of compulsive sexual behavior (eg, child molestation)
are legally reportable activities; others expose the patient to risk of arrest (eg,
exhibitionism). Still others increase individual risks of infection or physical
violence. All need to be empathically, but carefully assessed in any extended
evaluation.
In addition, careful review of ways in which PSB has impacted areas of
functioning is crucial. This starts with thorough review of medical history
(especially STIs), employment background and pattern, involvement with
alcohol and drugs (including nicotine and cannabis) that may be used before,
during, and after sexually compulsive behaviors, detailed history of legal
problems (whether formally charged or convicted or not), quality of relationships
with family, friends, and intimates (if any), and mental health functioning,
including both diagnosable psychiatric conditions and sub-threshold mood,
anxiety, and cognitive disturbances. This ancillary information provides strong
indications as to whether the behaviors indicating PSB are localized or are
generalized across multiple domains of functioning for the individual.
Over the past two decades, several measures have been developed, and
psychometric properties established for their use in providing valid and reliable
assays of PSB. Hook and colleagues (94) provide a comprehensive review of
seventeen published instruments assessing PSB. Scales include self-report
measures, clinician-administered measures, and a female-specific measure used
in gynecologic practice and research. Table 46-3 summarizes seven of the most
commonly used assessment measures of PSB symptoms used in the literature
and their psychometric properties.
TABLE 46-3 Frequently Used Measures of Problematic

Sexual Behavior
When selecting a measure, it’s vital to define its purpose. Screening instruments
are developed to be used with large samples to identify individuals in
mainstream populations who are more likely than others to have problems with
PSB. By contrast, measures of specific symptoms of PSB (eg, high-volume
sexual activities, paraphilia-defining behaviors) are more useful to assess
severity of a disorder in cross-sectional samples and response to treatment over
time in repeated measures. When assessing individuals from specific ethnic,
racial, or cultural groups, it is wise to select measures that have published data
describing their use within the particular group, if available.
Treatment Approaches
Treatment for individuals with PSB often occurs in the context of comorbid
substance use or psychiatric disorders and in the absence of randomized
controlled trials that might guide best practice. Instead, the clinician is faced
with a complex task of piecing together relevant findings from psychiatric
literature, small trials, and observational reports in order to arrive at an evidence-
informed, bio-psycho-social approach for intervention. There is some evidence
that for individuals whose PSB has strong obsessive–compulsive characteristics,
medications used to treat obsessive–compulsive disorder may relieve symptoms,
particularly the selective serotonin reuptake inhibitors (SSRIs) (100,101).
Another source of guidance involves early literature describing normal sexual
response and behavioral methods for addressing sexual dysfunction in couples
(102).
Contingency Management
There are no clinical studies applying the principles of contingency
management, that is, provision of increasingly valuable reinforcers for biological
data, demonstrating elimination of PSB. One explanation for this is that there are
currently no biomarkers that can reliably determine whether sexual behaviors
engaged are problems. On the other hand, among those individuals in treatment
for substance use, application of contingency management to reduce use of
substances highly linked to PSB, especially stimulants, reliably reduces
substance-related HIV- transmission behaviors (86,103).
Behavior Therapies
Behavioral approaches for treating PSB largely adapt models that have been
validated for treating substance use disorders (eg, cognitive behavioral therapy
[CBT], motivational interviewing) and apply these to the problems related to
PSB. Outcome reports on behavioral therapies come from open trials or case
reports, which provide feasibility information but scant information about
efficacy. This literature suggests that as in most behavior therapies, outpatient
treatments can help a significant proportion of individuals to remain in a help-
seeking process, to reduce levels of psychological distress, and to reduce
behaviors related to PSB, including reductions in numbers of sexual partners, in
episodes of public sex, and in combining drugs and alcohol with sex.
For individuals whose clinical distress and/or symptoms of PSB do not remit
from outpatient treatments, however, considerations of referral to levels of
inpatient care are appropriate. As with treatments for substance use disorders,
the quality of the literature documenting outcomes for residential treatment for
PSB is poor. One report showed that the majority (71%) of individuals followed
over a 4-year period relapsed to compulsive sexual behaviors, yet most reported
positive outcomes associated with retention in treatment (104). A small literature
describes integration of family therapies into inpatient and outpatient treatments
for PSB, though there are no data to describe treatment outcomes.
An important clinical issue in the management of these cases is how to
address the topic of the PSB with the couple and family. Female spouses/partners
of men with PSB are presented as having a central role in maintaining the
dysfunction of the compulsive sexual behaviors of the male. Some data describe
outcomes when disclosing PSB in families. Individuals in treatment for PSB
typically prefer not to disclose information to their spouses and/or children.
When female spouses (N = 63) learned of their husbands’ PSB, 75% did so by
accident; few found out via planned disclosures by the husband (105). Once the
disclosure is made, however, the impact on the women was traumatic regardless
of whether finding out accidentally or from a planned disclosure. Disclosures by
parents with PSB (N = 57) to children, whether made in anger or in unplanned or
forced disclosures (ie, someone threatened to tell), predictably caused upset in
the children. By contrast, planned disclosures allowed for forethought about
what information to tell the children and allow the discloser to emphasize the
amount of disturbance he has caused the family rather than provide accounts of
his behaviors.
Part of the treatment plan will usually involve some form of behavioral
treatment. In considering the outcome literature on behavioral therapies to
manage symptoms of PSB, the old bromide, “treatment works for who it works
for,” seems apt. Specifically, there is little direction from the literature that might
identify groups of patients for whom treatment works well or what might be
considered for the larger group of patients who terminate early or who show only
partial or wholly inadequate responses to treatment. This of course contrasts with
the interests of the criminal justice system to ensure complete elimination of
paraphilic behaviors for men who perpetrate sexual crimes against children or
nonconsenting adults.
Cognitive Behavioral Therapy
Cognitive behavioral therapy is a general approach to treating addictive
behavioral disorders that teaches patients skills to instill abstinence and to return
to abstinence upon relapse. The approach is highly didactic and involves the
counselor adopting the role of a coach for the patient. The approach also is
flexible and easily adapted to the needs of the clinician working with patients
seeking to eliminate problem symptoms related to their sexuality and to increase
sexual behaviors that are valued by the individual and his partners. CBT
approaches originate from social learning theory and conceptualize compulsive
sexual behaviors as being maintained both by exciting sexual experiences that
initiated and sustained the compulsive behaviors and by a lack of sexual
behavior experiences that are less extreme that are engaged in lieu of the
compulsive behaviors. One generic CBT strategy involves identification of
“triggers” (ie, persons, places, things, or internal experiences) that are specific to
sexually compulsive behavior. Other skills common to CBT also are applicable,
including distress tolerance (urge surfing), environmental manipulation (bans to
Internet access), diffusion techniques (mindfulness, meditation) and the like. An
important final point in using CBT approaches is that skills that help patients to
avoid problem symptoms are quickly mastered. Integrating substitution sexual
behaviors that are sufficiently acceptable and reinforcing to the patient in lieu of
more stimulating PSB requires most of the effort for the patient and the clinician.
There are no randomized controlled trials of CBT for PSB. There is,
however, one randomized controlled trial of CBT-based HIV-prevention
interventions for MSM. In MSM who completed baseline measures of sexual
compulsivity along with measures of sexual risk behaviors, no differences were
observed between the condition that received an HIV-prevention approach that
used CBT procedures and a standard condition. Post hoc analyses of these data
showed that MSM in the lowest and highest quartiles of the Sexual Compulsivity
Scale reported engaging in unprotected sex with status-unknown or presumed-
positive men at significantly higher rates than those in the interim quartiles
(106). The MATRIX adaptation noted above may also be helpful as a harm-
reduction strategy in this population.
12-Step and Self-Help Groups

There are no controlled studies of the efficacy of 12-step self-help groups in the
reduction of PSB, usually framed as “sexual addiction” or “sex and love
addiction.” The primary advantage to 12-step group attendance for those with
PSB is that the groups are convenient and widely available. The social process of
recovery, which involves selection of a “sponsor” to provide around the clock
assistance in managing sexual obsessions and compulsive urges, also assists
affected individuals to comply with the procedures of a 12-step program of
recovery. Moreover, while even the most efficacious program of psychotherapy
or of medication taken for the treatment of sexual addiction eventually ends,
involvement with a 12-step program for PSB can continue for many years.
Four 12-Step approaches have been adapted to assist individuals with PSB:
Sexaholics Anonymous, www.sa.org; Sex Addicts Anonymous, www.saa-
recovery.org; Sex and Love Addicts Anonymous, www.slaafws.org; and Sexual
Compulsives Anonymous, www.sca-recovery.org. The websites listed can assist
individuals seeking support in addition to ongoing psychotherapy and/or medical
treatment for PSB.
Psychoanalytic Approaches
Psychoanalysis has a long interest in paraphilic and hypersexual conditions,
tending to see both as particular, suboptimal responses to broader conflicts or
traumas during development, often a fixation in the oral stage or a narcissistic
injury (107). Psychoanalytic authors often implicitly or explicitly assume that
psychoanalysis can help with PSB, either by freeing up the fixations and
unconscious conflicts thought to motivate the compulsions (108), or by helping
patients come to terms with inappropriately negative or critical attitudes toward
their desires.
The term “sexual addiction” was first used in print by Fenichel in a larger
discussion of sexual perversions (109)–literally deviations from normal sexual
development. Kernberg discussed hypersexual aspects of borderline personality
disorder; like Melanie Klein (110), he saw them as reactions to unsatisfied oral-
dependent needs and pregenital aggression (111). Kohut (112) and his associates
saw compulsive sexual behavior as providing intense stimulation to reassure the
self of one’s vitality and reality, defending against depression, and attempting to
compensate for unmet narcissistic needs: “like all addictions, it is meant to do
away with a defect in the self, to cover it, or to fill it with frantic, forever
repeated activity” (113).
The efficacy of psychoanalytic treatment has more often been documented
with case reports than with large-scale, randomized, and/or manualized
controlled trials. Moreover, psychoanalysts are likely to see PSB as part of a
larger pattern of difficulties with aggression, dependency, toleration of affect, or
self-esteem, among other potential causes. Like other behavioral interventions,
psychoanalysis currently lacks systematic clinical trials supporting efficacy for
treatment of PSB specifically (114).
PHARMACOTHERAPY STRATEGIES
Antidepressants
One strategy for pharmacotherapy of PSB involves treatment of dysphoric mood
symptoms commonly experienced during initial (and perhaps sustained) sexual
abstinence. If antidepressant medications can diminish dysphoric mood
symptoms, patients may be able to sustain their sexual behavior goals. However,
there are no randomized, placebo-controlled trials of sexual behavior outcomes
(outside of adverse experiences) for patients treated with antidepressants other
than SSRIs. Instead, descriptive small and open-label trials and case reports
indicate that the medications can be used safely in this group.

Treatment of PSB with SSRI antidepressants is based on a hypothesized
underlying serotonergic dysfunction. Preclinical data show serotonin depletion in
the presence of testosterone greatly potentiates sexual behavior in laboratory
animals. More empirically, about 60% of patients receiving SSRIs can expect to
experience some form of treatment-emergent sexual dysfunction including all
phases of healthy sexual response: reductions in sexual desire, difficulties with
arousal, and delayed or absent orgasm. These effects appear to be related to 5-
HT2 receptor agonist effects and are not observed at the same rates in
medications with primarily noradrenergic mechanisms. In some penal systems
treating paraphilias, in-custody persons are given high doses of SSRIs to produce
dose-dependent sexual dysfunction as a side effect, a mostly unpublished
practice. SSRIs can cause hyperprolactinemia, which may reduce sexual
motivation and functioning. Evidence for this suggestion comes from the only
randomized, placebo-controlled trial of an SSRI for the treatment of PSB. MSM
rated as having compulsive sexual behaviors who were randomly assigned to 12
weeks of citalopram (20-60 mg/d) reported significant reductions in sexual
drive, in frequency of masturbation, and in viewing of pornography compared to
placebo (100).
Reports from small, open-label trials with SSRIs indicate the feasibility of a
particular medication approach. In one, 17 of 24 men with paraphilias and non–
paraphilia-related disorders treated with SSRIs showed sustained reductions,
over a minimum of 4 weeks, in total sexual occasions (101). Other open-label
trial experiences are consistent with positive outcomes in men who present for
treatment of PSB, with specifically poorer outcomes for men diagnosed with
paraphilic disorders as compared to men diagnosed with nonparaphilic disorders.
On balance, there is some initial controlled evidence supporting use of the
SSRI citalopram for PSB. At present, there is no evidence to support use of other
types of antidepressants to target reduction in mood dysphoria as a strategy for
treating PSB. When implementing this strategy in outpatient settings in
individuals seeking outpatient treatment for sexual behavior disorders, effects of
SSRIs on dampening libido and disrupting performance are general to all sexual
behaviors, not specific to the set of sexual behaviors that cause problems for the
individual. For this reason, ambivalence in the form of medication nonadherence
is common.
Opioid Antagonists
Naltrexone is an opioid antagonist approved for treating alcohol and opioid use
disorders. The putative mechanism of action for sexual compulsivity involves
dampening the opioid-dopamine reward system, thereby reducing the
euphorigenic properties of fantasy and sexual tension that are usually the initial
steps in compulsive sexual behaviors.
As yet, there are no large randomized, placebo-controlled trials of opioid
antagonists for PSB. An open-label trial of high-dose naltrexone (150-200 mg/d)
among adolescent sexual offenders was found to reduce PSB (masturbating 3 or
more times daily, reporting feelings of intrusive sexual thoughts or arousal,
spending more than 30% of waking time thinking about sex) in 15 of the 21
subjects. Naltrexone was tapered and stopped for administrative reasons in 13 of
the subjects, resulting in recurrence of the compulsive behaviors when
naltrexone dropped to 50 mg daily or lower (115). A placebo-controlled trial of
30 MSM with high rates of methamphetamine use, binge drinking, and risky
sexual behavior found that oral naltrexone 50 mg daily somewhat reduced all of
these behaviors (116). Especially for nonparaphilic disorders, naltrexone may be
a reasonable candidate for evaluation in clinical trials, but the lack of data makes
it premature to consider its use in clinical situations.
Hormonal Therapies for Paraphilic Disorders
Though the evidence base is still limited, pedophilic disorder in particular has a
larger body of evidence for treatment than other PSB. Because of public safety
considerations, more drastic interventions are sometimes considered for
pedophilic disorder and certain forms of sadistic paraphilic disorders than for
other forms of PSB.
A small number of open-label and case studies support use of androgen-
blocking medications for men with paraphilic disorders that involve children or
nonconsenting adults. Sometimes described as chemical castration, the anti-
testosterone strategy is usually reserved for treating men with paraphilic
disorders that involve sexual offenses involving children or violence against
adults. Cyproterone acetate and depot triptorelin have approved indications for
individuals with paraphilic disorders in some European nations (117). In the
absence of randomized controlled trials, reviews of observational studies and
open-label trials consistently show that these medications, as well as
medroxyprogesterone acetate and luteinizing hormone-releasing hormone,
effectively reduce additional offenses when taken as prescribed for up to 1 year,
particularly when implemented with CBT. When these men stop taking the
medications, their likelihood to offend returns to baseline levels (118).
The World Federation of Societies of Biological Psychiatry has issued
guidelines for the pharmacologic treatment of paraphilic disorders (119).
However, there is a conspicuous absence of well-controlled clinical trials, in part
due to reluctance to randomize forensic patients to a placebo condition. Based on
the available evidence, they suggest that SSRIs at higher doses typical for
obsessive–compulsive disorder may be useful. This guideline is rated as Level C
evidence, or “minimal research-based evidence to support this
recommendation.” Adding an anti-androgen agent to SSRI treatment is also
suggested, but the evidence supporting the recommendation is even lower (Level
D).
SUMMARY
A number of types of compulsive or ego-dystonic sexual behavior may come to
clinical attention, either at the initiative of the individual or their partner, or
through involvement in the legal system. These include paraphilias and
paraphilic disorders, concerns for excessive sexual desires and behaviors (high
numbers of partners, compulsive masturbation, compulsive pornography
consumption, etc.), and the combination of compulsive sexual behavior with the
use of drugs, particularly stimulants.
For persons referred to treatment in relation to crimes of a sexual nature, it is
important to keep in mind that most individuals with paraphilias do not commit
sexual crimes, and a majority of sexual crimes are likely committed by
individuals who do not meet criteria for a paraphilic disorder (60,61). Patients
with paraphilic disorders whose satisfaction entails sexual acts of a
nonconsensual nature or involving minor children may be candidates for
hormone-blocking therapies, and may be most appropriately referred to
specialist programs for further evaluation and treatment. It remains that sexual
orientation, including the orientation-like aspect of paraphilias, is highly
resistant to directed change through any known therapies. Treatment programs
thus often aim at drive reduction for those paraphilic disorders that may entail
harm to others, through SSRI antidepressants or hormone-blocking agents.
Though the concept of a general sexual addiction or hypersexual disorder
has a long history, it has not been supported by rigorous or replicated studies,
and has not so far produced evidence-based treatments. Research has been
compromised by arbitrary cutoffs and lack of consensus definitions. Critics have
noted frequent comorbidity of putative sexual addiction or hypersexual disorder
with psychiatric disorders, particularly bipolar disorder, substance use disorders,
and personality disorders. Many cases of self-diagnosed sexual addiction appear
to be influenced by strongly negative attitudes toward sexuality or particular
kinds of sexuality held by the individual or their partner, rather than clearly
demarcated by objective measures of sexual frequency or preference for
particular behaviors. Proposals for hypersexual disorder were rejected for DSM-
5.
Patients presenting with distress about their sexual behavior should also be
carefully assessed for paraphilias or paraphilic disorders, which may have more
specific treatments, though most of the evidence base is derived from forensic
samples.
Patients currently seek treatment for PSB including paraphilias and HVSB at
rates that are sufficient to support healthy practices and a burgeoning residential
recovery industry. Many addiction clinicians are willing to seek out evidence-
based (or at least evidence-informed) approaches to treating sexual behavior
disorders. Yet the evidence base is generally poor, requiring clinicians to knit
together bits of evidence into comprehensive bio-psycho-social approaches to
PSB. At minimum, there is evidence to support use of SSRIs, with or without
use of CBT. Comprehensive assessment is crucial to rule out comorbid
psychiatric conditions and to evaluate psychosocial factors that may contribute
to the behaviors or to the patient’s discomfort with them.
ACKNOWLEDGMENTS
The authors wish to acknowledge support from NIDA Grants P50 DA18185 and
T32 DA026400 and NIMH Grant P30 MH058107. Matthew Brensilver, PhD,
was coauthor on an earlier edition of this chapter.
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CHAPTER 47
Microprocessor-Based Disorders
Richard N. Rosenthal, Zebulon Charles Taintor, and Jon
E. Grant
CHAPTER OUTLINE
Introduction
Historical Perspective
Diagnostic Dilemmas
Assessment
Epidemiology and Comorbidity
Internet Characteristics
Treatment Model
Treatment Planning
Indications for Treatment
Pretreatment Issues
Relevant Treatment Research
Summary and Conclusions
INTRODUCTION
Microprocessors are all around us, serving as prosthetic brains, guides,
knowledge sources, calculators, temperature controllers, proximity alerters, and
the like, a technological leap of the late 20th century that is already having
profound effects on human functioning in the 21st century. Microprocessors help
us manage many aspects of our lives, and we use them a lot. They can provide
much stimulation, but ultimately, they do not manage our time, our motivations,
and our involvements, although some applications attempt to support these
things. Some of us use them too much, lose track of time while getting too
involved, and become habituated to the stimulation they provide. Some of us
have significant negative life consequences as a result of that level of
engagement, not that different from addiction to substances, which in itself is a
topic of debate. This chapter is about the use of microprocessors, their
substrates, and the problems that can ensue. These purported addictive disorders
are supported by the microprocessors that have made this all possible and where
the bulk of activity is conducted on the Internet. However, people are addicted
not to the microprocessors, any more than the electricity that powers their
smartphones and computers, but rather to what substrates the devices provide.
Then, the main question is one of demonstrating the validity of Internet use–type
disorder and/or more specific disorder substrates such as gaming, gambling, and
sex or social networking.
The Internet has six major uses that affect clinicians and their patients: (a)
source of information on disease, diagnosis, treatments, and therapists; (b)
support and self-help groups (moderated or not); (c) provision of advice,
diagnosis, and counseling whereby the person being helped has not met the
helper except over the Internet; (d) obtaining addictive substances, both
prescription and nonprescription; (e) supporting a platform for individual or
group engagement in novel constructs such as social media and online gaming;
and (f) enhanced opportunities for people to do things that would tend to bring
them to the attention of a clinician even if they did not happen to use the Internet
(sex, gambling, etc.). Some of these last activities are regarded as addicting in
their own right and will be discussed further.
The term “Internet addiction” covers only part of the problems encountered
by clinicians in patients who spend too much time using devices built around
microprocessors. Consider the accident resulting from instant messaging (IM)
while driving, the gunshots exchanged over Xbox use, too many hours on the
Internet using a mobile phone, or a person who finds Second Life more real than
his or her real life. The common denominator is the use of microprocessors in an
increasingly wide variety of devices. What is clear is that the human problems
that are now becoming apparent in the context of microprocessor use are related
to the interaction of the novel technology and the people using it, as compared to
intrinsic mental disorders that have been around for millennia, such as
depression and schizophrenia, or other disorders of compulsive/impulsive
behavior such as eating disorders or pathological gambling. Yet, as will be
discussed below, much of the impairing use of microprocessors appears to
conform, with respect to predisposing factors, cognitive function, comorbidities,
and neurobiological and neuropsychological correlates, to that of substance use
disorder (SUD) and other behavioral addiction. Research attention to the broad
category of Internet addiction has burgeoned since the American Psychiatric
Association announced that it would place Internet Gaming Disorder (IGD) into
Section 3 of DSM-5 (1). In fact, of the 2135 articles listed from 1996 for
“Internet Addiction” on PubMed (https://www.ncbi.nlm.nih.gov/pubmed) as of
July 16, 2017, almost 70% have been published since 2012 and a large
proportion of which is focused on IGD.
HISTORICAL PERSPECTIVE
The history that matters is the most recent, as the pace of change has been so
fast. The Internet was established in 1969 at the University of Southern
California as a way of linking computers for national defense uses. Even early
on, computers offered opportunities to impair functioning, even in the absence of
the Internet. Weinberg (2) described programmers so immersed in programming
they failed to properly document their work. Later, Weizenbaum (3) described
the development of compulsive programmers who had lost the broad view of
problem-solving and came to see problems simply as means to interact with the
computer. The concept of the impaired computer user was described in 1992 by
Kuiper (4), who called them “space cadets,” characterized as spending too much
time in front of industrial or commercial computers and having too few other
ambitions or interests. Once the Internet became functional in the business
community, it did not take long for it to become an instrument of non–work-
related use in the workplace, problematic if not necessarily pathological. A
survey of 224 US companies by Greenfield and Davis (5) demonstrated that 60%
of companies had disciplined employees about inappropriate Internet use and
30% had terminated employees owing to Internet behavior. Forty-seven percent
of a randomly selected group of workers from the 224 companies surfed non–
work-related websites more than 3 hours per week and 19% 4 or more hours per
week (5).
Specialized offers to certain customers via email began in 1973, and the first
online service among for people who used computers started in 1979. Use of
email for therapy was documented in the 1980s, and simulated patients were
developed (eg, “Eliza” and “Parry”) to demonstrate typical psychopathology to
those who signed on to interact with them. But widespread use of email
skyrocketed in the 1990s as email programs became interoperable, and anyone
was able to get and send from any of a variety of software programs. The first
wave of articles about Internet addiction appeared in the mid-1990s, and the
Center for Internet Addiction Recovery was one of dozens of sites set up to help
the addicted. A book by its founder, Kimberly Young, PsyD, provides a picture
of Internet addiction in the late 1990s (6). Text and IM took off as the 21st
century began with personal digital assistants (PDAs), BlackBerrys, and
increasingly smart cellular telephones. By 2012, it was estimated that 94% of the
American population had fixed broadband access to the Internet, including 80%
of households with download speeds as high as 100 Mbps, although ~100
million Americans were not yet subscribers where broadband is available, citing
perceived lack of usefulness, lack of digital literacy, and unaffordability (7).
Modern cellular telephones typically include a wide variety of communication
modes such as Internet, email, and messaging capability (“smartphones”) as well
as multiple sensor arrays and geolocation capacity. Year 2010, U.S. Census data
had 74% of the American population having Internet access (8). By 2015, 84%
of US adults used the Internet compared to 52% in 2000, with highest adoption
rates among young adults (9). Home broadband Internet adoption plateaued at
67% but with an adoption rate of 68% for smartphones, where 13% use only
their smartphone to access the Internet (10). Of the 95% of Americans that own
a cell phone, only 18% do not use a smartphone (10). America Online’s Fourth
Annual Survey of people who use email (in 2008) found an increase in 1 year
from 15% to 46% of self-described “email addicts,” who check email in bed
(67%), in the bathroom (59%), while driving (50%, up from 37% in 2007), and
church (15%) (11). Yet, now these data seem quaint, given the profound
integration of microprocessors into daily life in smartphones and tablets used for
communications. Culture has evolved, too: by 2017, texting while driving is
illegal in 46 states and the District of Columbia.
Social Adaptation to Technological Change

It is important to recognize that some portion of what has been thought as
problematic use of microprocessors may have to do more with social adaptation
to new technology than with psychopathology. Forming new relationships with
fellow online computer users may have once represented eccentric or problem
behavior, but the advent of Internet social utilities such as social networks,
commercial dating sites, special interest blogs, chats, and others has made this a
mainstream activity (12). Similarly, checking one’s email before something else
that you need to do is a more mainstream behavior, now that Internet access is
ubiquitously available on wireless as well as wired and cabled devices (12).
Constant feeds of information from Twitter, Snapchat, Facebook, and Instagram
provide a need for social adaptation that was unimagined by most in the past
except science fiction authors and writers of dystopian novels.
Identity and the Internet are emerging as a separate field of study due to the
impact of Internet-based applications and social networking sites. Participation
in alternate realities offers rich material for considering identity choices and
psychodynamics, although false identities and misrepresentations abound in
social media such as Facebook, where there were an estimated 2.01 billion
monthly active Facebook users for June 2017. Second Life, an online virtual
reality application where one could construct a complete interactive identity
capable of interpersonal and financial transactions (www.secondlife.com), at its
peak, had 51 million users of their content (13), and people had reported having
more success in Second Life than in their real lives (14). Other patients have
entered therapy because of social media–based relationships gone awry.
As any assessment of addiction involves considering risk-taking behavior, it
is important for clinicians to understand the current risks that the use of
microprocessors offers. One can easily become a victim when participating in
email and chat groups wherein others are using false identities, often for a
specific purpose such as sexual predation. Technology change has outstripped
the legal system’s ability to provide basic protections. Even where economic
damages can be claimed, such as false information engendering stock price
swings, prosecution has been scant. Meanwhile, there are almost daily reports of
data security breaches involving thousands of people (see http://datalossdb.org/).
It is also important to consider developmental vulnerability, as novel technology
may carry downstream consequences for those exposed early in childhood.
Parents are often limited by technological naïveté from understanding what their
children may be experiencing and doing, adding a dimension of complication to
the evaluation they may present. For example, in considering the potential risks
of media exposure, the American Academy of Pediatrics (15) suggests no
exposure to screen media at all for babies younger than 18 months except for
live video chat, to avoid solo media use in children 15 months to 2 years, and to
limit screen use to 1 hour per day of high-quality programming for children 2-5
years of age. Children below 2 years spend 2 hours per day on average with
screen media, yet there is evidence of poorer word learning with “educational”
on-screen media when viewing is unaccompanied (16).
DIAGNOSTIC DILEMMAS
There has been an animated discussion of terms such as “Internet addiction,”
“pathological computer use,” “pathological Internet use (PIU),” “compulsive
Internet use,” “email addiction” (see above), and the like in the popular press,
where the concept of addiction is used to describe a much less serious
phenomenon than what clinicians usually mean by “addiction.” With increasing
use of microprocessors, the terms have progressed from being jokes to being
taken seriously. In considering whether the microprocessors are a bona fide
substrate for addictive processes, it is important to present some caveats:
Using the computer, cell phone, or video game is not intrinsically illegal,
although the media can be used for that purpose.
Using the computer, cell phone, or video game is generally normal,
prosocial, encouraged behavior.
For many people, microprocessor use is a source of frequent high
engagement that is not pathological.
There is a learning curve to information acquisition, time management, and
social behavior when people experience these new and powerful tools
(think about pedestrians walking in city streets holding their cell phones
that block their view of oncoming traffic or listening to iPods, which
attenuate their ability to hear important external auditory cues).
Calling maladaptive microprocessor-related behavior pathological rather
than, say, a bad habit may medicalize what is in actuality a social problem.
Unanswered questions thus arise in the context of considering whether Internet

addiction is a discrete disorder and whether it is an addiction or some other type
of disorder:
Are most surveys that present high rates of PIU suffering from selection
bias?
Is the term Internet addiction overstated and overgeneralized (ie, are there
too many false positives determined by current screening instruments)?
Is it the technology or that contact or behavior that it enables that people
may become addicted to?
Does the use of the Internet as a conduit for other disorders such as
pathological gambling or compulsive sexual behavior become in itself a
substrate for addictive process?
Is Internet addiction a component of another disorder, or if a discrete
disorder, does it frequently co-occur with other mental disorders?
Martin and Petry (17) debated whether non–substance-related addictions (ie,

behavioral addiction) were really addiction. In this debate, Martin pointed out
that addiction as a process requires transformation of basic survival-oriented
drives into misdirected or overly frequent actions that leave less time for more
adaptive functioning. Recent research suggests that this process is also seen with
Internet-related impairments (18–20). A more recent debate has focused on
whether Internet addiction is a separate and internally consistent though
generalized disorder or a catch-all that contains several separate but related
disorders supported through Internet-based activity, such as IGD (1) and
proposed others related to impairing use of Internet-supported gambling,
pornography, and other activities (21,22). Griffiths (23,24) conceptualizes this
distinction as addiction to the Internet and addiction on the Internet. A similar
distinction was made by Davis (25) in considering PIU, positing a generalized
form and a specific form that corresponded to individual disorders accessed
through the Internet and related to gambling, gaming, cybersex, etc. Analysis of
treatment-seeking patients at a behavioral addiction clinic supports a range of
different primary substrates such as gaming, chatting, or sexual content for those
seeking treatment for PIU defined as a score > 70 on the Internet addiction test
(IAT) (26). More recently, Brand et al. (19,27) have reframed Internet addiction
as Internet use disorder, which, as a behavioral addiction, might eventually be
included in the substance-related and substance use disorders section of DSM-5
(as gambling disorder has been) and, analogous to various specific SUD, allow
for specific use disorders such as IGD, Internet gambling disorder, Internet
pornography viewing disorder, and so on. Dong and Potenza (28) proposed a
cognitive–behavioral model to elucidate IGD that contained 3 components
including motivational drives related to stress reduction and reward-seeking,
such as enhanced reward sensitivity and decreased loss sensitivity, deficits in
executive control and related response inhibition, and process that relates to the
decisional balance between choosing to act on and refrain from a motivated
behavior. They further hypothesized that therapeutic approaches specific to these
described IGD-related deficits could be addressed with corresponding forms:
cognitive–behavioral therapy (CBT) for strengthening recognition of
maladaptive cognitions and improving inhibitory control; cognitive enhancement
therapy to improve response inhibition, cognitive flexibility and problem-
solving, and capacity for delayed gratification; and cognitive bias modification,
which could address cognitive processes such as attention bias and approach bias
toward Internet-related cues (28).
Brand et al. (19) have further developed their model of Internet use disorders
to integrate the motivational domains presented in Dong and Potenza (28) and
propose that, similar to drug of choice determinations among those with SUD,
among those with specific instances of Internet use disorder, there will be a “first
choice use” of the genre of applications supported by the Internet, such as
pornography/cybersex, gaming, gambling, social networking, etc. They further
propose the Interaction of Person-Affect-Cognition-Execution or “I-PACE”
model of specific Internet use disorders that includes predisposing core
characteristics of the person together with genetic, temperamental, personality,
and psychopathological traits that render vulnerability; affective and cognitive
reactivity to internal or external stimuli that render vulnerability to specific
forms of stimulus, in addition to the impact of maladaptive coping strategies,
attentional bias toward Internet-related cues, the deficient capacity for mood
regulation, and development of cue reactivity and craving; and the impact of
deficient executive functions and/or inhibitory control on the development and
maintenance of Internet use disorders (19).
Neuroimaging and Neuropsychological

Correlates
Internet Addiction Disorder
Internet addiction disorder (IAD) was initially codified by Young (29) as an
eight-item polythetic diagnostic set modeled on pathological gambling.
Neuroimaging research has begun to examine neural underpinnings of IAD.
Studies thus far have demonstrated altered regional cerebral activity and
structural changes associated with IAD in ways generally consistent with studies
of drug and behavioral addiction (30). Positron emission tomography studies
have demonstrated that compared with normal individuals, those with IAD have
increased glucose metabolism in the right orbitofrontal cortex, the left caudate,
and the right insula and decreased metabolism in the bilateral postcentral gyrus,
the left precentral gyrus, and the bilateral occipital regions (31) and, in men,
decreased dorsal striatal dopamine D2 receptor availability that is inversely
correlated with IAD severity, consistent with the substrates of reward deficiency
hypothesized in SUD (32). Among adolescents (n = 18) with IAD, Yuan and
colleagues demonstrated that decreased gray matter volumes in the bilateral
dorsolateral prefrontal cortex, the supplementary motor area, and the left rostral
anterior cingulate cortex (rACC) as measured through voxel-based morphometry
and increased white matter fractional anisotropy of the left posterior limb of the
internal capsule as measured through diffusion tensor imaging were significantly
correlated with the duration of Internet addiction (33). Hong et al. (34) used R-
fMRI to evaluate whole brain connectivity in adolescents with IAD and
demonstrated significant and broad decrease of functional connectivity in
corticostriatal circuits with the bilateral putamen being the most affected
subcortical brain region. Similarly, Lin et al. (35) used R-fMRI to examine the
integrity of corticostriatal circuits in adolescents with IAD compared to healthy
controls and demonstrated reductions in connectivity of corticostriatal functional
circuits involved in cognitive control and affective and motivation processing.
Specifically, reductions in functional connectivity were found between the
inferior ventral striatum and caudate head, subcallosal anterior cingulate cortex
(ACC), and posterior cingulate cortex bilaterally, between the superior ventral
striatum and bilateral dorsal/rostral ACC and ventral anterior thalamus, and
between the dorsal caudate and dorsal/rostral ACC bilaterally as well as other
regions involved in cognitive control (35). Higher severity of IAD was
significantly correlated with lower functional connectivity between the right
superior ventral striatum and the dorsal caudate bilaterally (35). Resting state
functional magnetic resonance imaging (R-fMRI) was used to evaluate brain
functional connectivity in adolescents with IAD and excessive online gaming
compared to healthy controls and demonstrated significant disruption in the
functional connectome, particularly between regions located in the frontal,
occipital, and parietal lobes. The affected long-range and interhemispheric
connections correlated with the IAD severity, and behavioral clinical
assessments suggest that IAD may disrupt functional connectivity linked to
behavioral impairments (36). In addition, there appear to be differences in
cortical structure between adolescents with IAD and healthy controls. Hong et
al. (37) examined the thickness of orbitofrontal cortex (OFC) with MRI and
found that the right lateral OFC of adolescent males with Internet addiction have
significantly decreased cortical thickness (p < 0.05). These results suggest that
long-term IAD may lead to structural brain changes and altered function,
although a causal relationship has not yet been established. However, one might
expect increased coherence in tracts carrying information about finger
movement and motor imagery (posterior limb of the internal capsule) given the
man-hours those deeply immersed in Internet gaming spend on game play with
manipulation of keyboards, mice, and/or joysticks.
Our understanding of the neurobiological basis of Internet addiction is
progressing (for a detailed review, see ref. (38). Internet addiction has been
associated with structural and functional abnormalities in the orbitofrontal,
dorsolateral prefrontal, anterior cingulate, and posterior cingulate cortices;
regions that play crucial roles in salience attribution, inhibitory control, and
decision-making.
Internet Gaming Disorder

Moving a step beyond IAD, recent research has examined the more particular
version of IAD focusing on Internet gaming. Whether IGD should be regarded
as a mental health problem distinct from IAD awaits greater understanding at
this time, but recent imaging studies have begun to paint a picture of a unique
behavioral addiction. Dong et al. (39) examined neural correlates of response
inhibition using event-related functional magnetic resonance imaging (fMRI) in
24 males without SUD performing the Stroop task; among the group (n = 12)
who had Internet gaming–related IAD (score > 80 on the Internet addiction test)
(40), there was greater activity in the anterior and posterior cingulate cortices,
consistent with impaired inhibitory control and decreased cognitive efficiency of
response inhibition processes (39). In addition, among Internet gamers with
IAD, diffusion tensor imaging demonstrated abnormalities in the posterior
cingulate cortex and thalamus with higher fractional anisotropy in the thalamus
associated with greater severity of Internet addiction (41). More recently, a study
of 41 men with IGD examined neural processes underlying impaired decision-
making related to gains and losses and found that the IGD group, compared to
healthy controls, showed weaker modulation for experienced risk within the
bilateral dorsolateral prefrontal cortex and inferior parietal lobule for potential
losses (42). In addition, during outcome processing, the IGD group presented
greater responses for the experienced reward within the ventral striatum,
ventromedial prefrontal cortex, and OFC for potential gains (42).
Recent functional neuroimaging studies have demonstrated that adolescents
with IGD exhibit aberrant activations in the frontostriatal network, the
supplemental motor area, the cingulate cortex, the insula, and the parietal lobes
(43,44). Additionally, there is a suggestion of dysfunction in functional
connectivity in the resting state between multiple brain regions (45,46) and that
this dysfunction is associated with greater impulsivity (47). Other structural
imaging suggests decreased gray matter volumes and altered white matter
integrity in areas involved in inhibition and emotional regulation (48–50).
In considering whether Internet addiction is a real disorder, an approach
different from the DSM-5 polythetic approach may be useful in creating a
narrow construct within which to categorize Internet addiction. In a monothetic
approach, all criteria must be endorsed in order to give a diagnosis, and it should
have high sensitivity for diagnosing true positives. If a monothetic approach can
be constructed that has good construct and predictive validity, then expanding
out from that may allow a criterion set that has reasonable clinical utility in
reducing false negatives. Griffiths (51), in considering the necessary components
of addiction that would subtend diagnostically both substance and behavioral
addiction, identified six necessary domains based on the work of Brown (52,53)
in modeling problem gambling behavior: salience, mood modification, tolerance,
withdrawal symptoms, conflict, and relapse. This method is interesting, and
clinicians who treat patients with substance use disorders will recognize the
symptom set in their patients and thus the economy in the approach:
Salience: The drug or behavior has gained primacy in a person’s life, which
can be a cognitive change, dominating the person’s mental life or,
behaviorally, dominating a person’s activity in a compulsive fashion.
Mood modification: The substance or behavior subjectively gives one a
rewarding high or alleviates a negative mood state.
Tolerance: The person must increase the amount or intensity of the
substance or behavior in order to achieve the desired effect.
Withdrawal symptoms: After stopping or reducing the substance or
behavior, the person demonstrates either physical symptoms after or
dysphoria characterized by irritability, mood lability, depressive symptoms,
and so on.
Conflict: The person has conflicts regarding the use of the substance or the
behavior that manifests as either interpersonal (eg, marital strife) or
intrapsychic (eg, guilt).
Relapse: After a period of abstinence, the use or behavior is reinstated with
the same intensity.
Proponents of a polythetic approach to Internet addiction modeled after DSM-5

substance use disorder might point out that one of the hallmarks of the modern
concept of addiction is the idea of loss of control despite negative consequences,
which is embodied in several of the DSM-5 criteria and not included as one of
the six necessary domains of the monothetic approach. However, compulsive
behavior in the salience category accounts for the symptom of loss of control.
It may be argued that problematic Internet use better fits criteria for DSM-5
disorder groups other than the substance-related disorders (ie, Internet
addiction). This is what was behind the differing nomenclature, such as
Pathological Internet Use, which is modeled after pathological gambling, which
was an impulse control disorder (ICD) diagnosis in DSM-IV but which as
gambling disorder has been moved to the substance-related and addiction
disorders in DSM-5 (1). For example, PIU has been proposed as an obsessive–
compulsive disorder (OCD) spectrum disorder. However, in compulsive
disorders such as OCD, the intrusive thoughts or compulsive behaviors are
typically ego-dystonic, whereas in PIU, the preoccupation is ego-syntonic and
pleasurable. While most patients with OCD are anxious and full of doubt and
tend to avoid risk, others dispel their obsessions and resultant anxieties through
compulsive Internet use (CIU). Patients with unhealthy Internet use tend to
underestimate risk. Shapira et al. (54), using the Structured Clinical Interview for
DSM-IV (SCID), Internet use history, and a Yale-Brown Obsessive Compulsive
Scale modified for Internet use, examined 20 recruited volunteers or referred
patients with problematic Internet use characterized as uncontrollable, markedly
distressing, time-consuming, or resulting in social, occupational, or financial
difficulties and not solely present during hypomanic or manic symptoms. In
general, the subjects had, in contrast to patients with compulsive disorders, low
levels of distress and resistance to excessive Internet use. Their problematic
Internet use symptoms were highly impulsive, with all subjects meeting DSM-IV
criteria for an ICD not otherwise specified, whereas only 15% subjects met
DSM-IV criteria for OCD based on their problematic Internet use. However, this
uncontrolled study had a small sample size and a clear selection bias, so
generalizing from the results may be problematic. Nonetheless, like pathological
gambling, PIU could be conceived as an ICD, and several authors have proposed
this (5,55–57). In fact, a cross-sectional association analysis of n = 81 subjects
equally grouped into IAD, pathological gambling, and normal controls revealed
that those with IAD have increased trait impulsivity comparable to those with
pathological gambling and a positive correlation of trait impulsivity to IAD
severity (58). Similarly, Meerkerk et al. (59) explored personality correlates
predictive of CIU, an IAD proxy, and demonstrated in a survey among n = 304
respondents who met the criteria (score > 28) on the Compulsive Internet Use
Scale (CIUS) (60) that dysfunctional impulsivity (ie, rash spontaneous, including
constructs of novelty seeking, sensation seeking, behavioral undercontrol, and
disinhibition) was the strongest predictor of CIU compared to reward or
punishment sensitivity (59).
Hallmarks of ICD are repeated failure to resist impulses that are harmful to
self or others and tension or arousal before and pleasure or relief during the act,
followed by guilt or self-reproach. However, this may not necessarily be the case
in patients with problematic Internet use and will need to be explored with larger
epidemiological studies and more refined research of potential diagnostic
criteria. In addition to symptoms that overlap with impulse control disorders (eg,
intense preoccupation with Internet use, CIU, loss of control over online time),
however, Internet addiction also shares symptoms with behavioral addiction,
such as development of euphoria, craving, and tolerance (61). The DSM-5
workgroup had at one point been contemplating problematic Internet use as a
compulsive–impulsive disorder in the group of ICDs (57). As such, it may be
that the placement of what may be considered Internet addiction among the
DSM-IV impulse disorders was an artifact of the failure to expand the category
of substance-related disorders to broader diagnostic category that includes non–
substance-related “behavioral addiction.” The monothetic approach to addiction
described above supplies one potential model for building that category (51).
The utility of a monothetic approach is that in requiring all symptoms to be
present, if any subgroup of those with problematic Internet use fits the criteria,
then the high specificity should make it easier to validate as a disorder. In order
to provide construct validity of the monothetic model, it remains to objectively
demonstrate tolerance and perhaps physiological or neuroimaging concomitants
of withdrawal that are more than reported withdrawal-related dysphoria
(although dysphoria may be sufficient for a polythetic approach, as it is in
pathological gambling) (62). Assuming high construct validity, if anyone has
Internet addiction, it is someone who meets monothetic criteria. As is, in DSM-5,
IGD has been pulled from the more inclusive concept of Internet addiction and
placed in Section 3 with the other “Conditions for Further Study,” and the
placement of gambling disorder in the substance-related disorders raises the
possibility of other behavioral addiction ultimately being validated as belonging
to that group, modeled on “use disorders”(1). Recent work by Brand et al. (19)
and others further supports this notion, and the American Society of Addiction
Medicine has formally included non–substance-related behavioral patterns of
pursuing reward or relief in its definition of addiction (63).
Another approach to developing stable and valid criteria for Internet
addiction has been to build a bottom-up construct of most frequent symptoms
from factor analysis of a group. Pratarelli and Browne (64) conducted a 94-item
anonymous survey in college students (n = 524) and demonstrated the
nonindependent factors: Internet addiction (preoccupation, external complaints,
less sleep, food, exercise, and punctuality) (salience), sexual (downloading
graphic sexual material), and an Internet use factor (excessive use for
professional, educational, gaming, shopping activities, etc.). When the data were
best fit to a structural equation model, the addiction factor was primary and
causal to sex and use factors rather than vice versa. Charlton (65) performed a
factor analysis on 47 variables derived from the six-factor monothetic model of
addiction described above (51–53), with added items that evaluated engagement
(computer apathy/engagement and computer anxiety/comfort) from data
collected from a survey of 404 college and graduate students. The addiction
factor loaded upon all items of the monothetic model behavioral addiction
criteria supporting the construct validity of this model of computer addiction
(65). However, the engagement factor also loaded upon tolerance, euphoria, and
cognitive salience, demonstrating that these factors are not unique to addiction.
This suggests that high computer engagement is part of the structure of
“computer (includes Internet) addiction” but is not necessarily pathological in
and of itself. One can be highly engaged in Internet use without negative
consequences. Beard and Wolf (66) describe a woman who is preoccupied by
thoughts; desires increased time spent in activity; is unsuccessful or unable to
control or cut back interactions; is restless, anxious, or moody when not
interacting; and interacts for longer periods than intended. Without a defined
substrate, the symptoms seem ominous in the example above, but the high
engagement of this woman for her baby is not pathological, and the authors
suggest that additional requirement of impairment in a person’s daily functioning
(ie, jeopardized loss of relationship or work/educational opportunity, lied to
significant others to conceal extent of Internet involvement, or used the Internet
so as to escape problems or relieve dysphoria), over and above symptoms of
high engagement, is necessary for a diagnosis of Internet addiction (66). This
finding is paralleled in the work of Ko et al. (67), who in establishing a criterion
set for adolescent Internet addiction that had high diagnostic accuracy and
specificity, as well as good sensitivity, determined three main criteria:
characteristic symptoms of Internet addiction not dissimilar from DSM-IV
substance dependence symptoms, an exclusion criterion, and functional
impairment due to Internet use.
Since the Internet is here to stay, future work will need to differentiate the
substrates of behavioral addiction from an overall diagnosis of IAD, much as
SUDs are classified according to substance used, for example, alcohol,
stimulants, and sedative–hypnotics. The most likely domains are static and live
sexual content (frequently in the context of co-occurring stimulant and other use
disorders), video gaming, and gambling/day trading and perhaps social
networking/live interfacing (including chat, texting, video), shopping/auctions,
netsurfing, and music/video downloading/torrenting. An interesting need for
differentiating purported behavioral addiction such as “sex addiction” and those
that are solely microprocessor-based will occur at some point and represents a
similar problem to that of the more inclusive IAD diagnostic range and the
narrower, substrate-based concepts, such as IGD. At present, only IGD is
included as a proposed diagnostic category in Section 3 of DSM-5. Much as
social networking is a recently invented phenomenon, there may be future
Internet applications that end up as new substrates for Internet addiction.
Inquisitive individuals are at risk for “falling down the Wiki rabbit hole” because
the hypertext content links can bring one to interesting new content pages in an
infinite regress, but evidence of this at a disorder level has not yet been reported.
Recent evaluations of social network sites demonstrate that they are used for
social purposes, mostly related to maintenance of already established offline
networks, and there has been scant documentation of pathological use (68). Kuss
and Griffiths (68) identified interesting correlates of social networking related to
increased use, such as social enhancement in extraverts with high self-esteem
and social compensation in introverts with low self-esteem, as well as high
narcissism and low conscientiousness. In addition, they found correlates that
might signal addiction vulnerability, such as decreases in academic achievement,
non-Internet community participation, and relationship problems.
Substance addictions occur at high rates with other mental disorders in the
population, so it would not be surprising to see a related pattern in those with
behavioral addiction (69). Carli et al. (70) conducted a systematic review of 20
studies of the correlation of PIU, as assessed by the IAT and other scales, with
other psychopathology and found, among the mostly Asian cross-sectional
studies, consistent and strong correlation of PIU with attention deficit
hyperactivity disorder (ADHD) and depression. Among online gamers (n = 722)
who filled out a survey questionnaire, weekly online gaming time was averaged
28.2 ± 19.7 hours and was significantly and linearly associated with severity of
depression, social phobia, as well as Internet addiction scores (71).
ASSESSMENT
Talking to patients, one can discuss the intensity and impact of their use of
microprocessor-containing devices and assign general risk categories based upon
the information provided. A simple screening cutoff can begin to establish
whether use is “normal” or unhealthy. From there, it becomes more difficult to
establish what one is dealing with, owing to the lack of scientific consensus as to
whether certain types of unhealthy microprocessor use rise to the level of
disorders, what type of disorders they may be, and what the criteria are for those
disorders. As discussed above, functional impairment is a good marker for a
clinically relevant use of microprocessors (72). Below is an attempt to broadly
define various severity levels of microprocessor use.
Use: A reasonable time spent accomplishing specific goals using
microprocessors, such as a Google search on “pathological computer use”
(2,230,000 results in 2017—more than nine times that cited in the 2014 edition
of 243,000) or getting back your dog that strayed because the staff at the pound
found the chip under his skin with your name and telephone number. Remember
that high engagement does not necessarily mean pathology.
Problem use: One can conceptualize this as use with trouble in that the use is
causing clinically significant impairment. The issue here is the repeated taking
on of undue risk, getting oneself into legal problems, the interference with
fulfilling major role obligations, or continuing the microprocessor use in spite of
recurring social or interpersonal problems. These parallel the prior substance
abuse category for the DSM-IV substance-related disorders and might present as
subthreshold for DSM-5 IGD, for example, when the syndrome causes
impairment but <5 of the criteria are endorsed for a 12-month period. IM while
driving is risk taking and illegal in most states yet emerging as more accident
related in some jurisdictions than a handheld cell phone. A mother showed
author ZT her initial failure to limit her daughter’s IMs to 500/d—one printout
showed more than 3000—“She is here but she is not here.”
Use disorder: The patient experiences that he or she cannot get along without
it. Here, the problem is the level of functioning. Can we get by without the facts
so easily pulled off the Internet? Can you calculate as well or as fast as your
spreadsheet? Can you avoid email for a day a week, as is increasingly
recommended in the popular press? As with most disorders, there may be a false
sense of being in control and “able to stop any time” when, actually, one cannot.
Consistent with DSM-5 substance use disorder, a syndrome akin to
substance withdrawal may become evident. Symptoms such as nervousness,
aggression, agitation, insomnia, anorexia, tremulousness, and depression have
been noted after microprocessor-based device deprivation. Craving, newly part
of the DSM-5 criteria for SUD, has also been demonstrated in IAD (19,61) and
can be purposely elicited by cues and targeted for treatment (73,74). While one
can argue that use of an exogenous substance is necessary to produce the
physiological changes of true addiction, it is increasingly evident that the body
and brain change in response to the environment. Whereas the brain is composed
of chemicals, its final pathway of action is electrical, and input from computers
increasingly taps into cerebral rhythms. Virtual reality, use of smell, more
sophisticated visual and auditory inputs (eg, augmented reality), and probably
other paths into the brain will increase influence on the brain. However, at least
one study found surprisingly that the interactive functions of the Internet are not
as addictive as other functions such as salience, lack of control, or anticipation
(75). SUD can result from buying addictive substances through the Internet,
where enforcement has been unsuccessful against thousands of sites offering
prescription drugs and a handful of sites openly offering cocaine, heroin,
synthetic cannabinoids, and other illegal substances (76).
EPIDEMIOLOGY AND COMORBIDITY
The problem of understanding the prevalence of Internet addiction and related
use disorders has its origin in the lack of internationally agreed upon
standardized approaches to diagnosis, the multiplicity of instruments used to
assess Internet-related psychopathology, and a deficit of large community-based
studies. Some ground has been covered with the addition of IGD and its
standardized set of criteria to the DSM-5. Cheng and Li (77) conducted a meta-
analysis of N = 80 studies of Internet addiction published in 1996-2012 from 31
countries and 7 world regions that used the IAT or the Young Diagnostic
Questionnaire and generated a global base rate estimate of 6% (but without
African data) with regional differences such as 10.9% in the Middle East, 8% in
North America, and 2.6% in Northern and Western Europe. However, Kuss et al.
(78) conducted a systematic review of epidemiological research into the
prevalence of Internet addiction and found that broad regional variations in
prevalence rates such as 0.8% in Italy as compared to 26.7% in Hong Kong were
a consequence of differing assessments with different cutoff thresholds.
Nonetheless, the authors observed that there were some replicable core
symptoms across studies such as compulsive use, preoccupation/salience, and
negative consequences, which should likely be included in the core criteria for
the construct validity of the diagnosis (78). Rumpf et al. (79) administered the
Compulsive Internet Use Scale (CIUS) (a proxy for Internet addiction addressing
symptoms of salience, withdrawal, loss of control, conflict, and coping with
unpleasant mood) by telephone to 8130 randomly dialed German respondents
(ages 14-64) who used the Internet privately for at least 1 hour per day, in order
to estimate Internet addiction prevalence rates, finding overall 4.6% at risk for
and 1% with Internet addiction, increasing to 2.4% among 14-24-year-olds and
4% among those ages 14-16. The overall risk was more than doubled for those
recruited with mobile-only numbers versus access to landline connections,
consistent with higher mobile Internet access among youth. The base prevalence
of IAD in the German sample is consistent with other studies of IAD that
surveyed the general population in the United States, 0.7% (80), and in Norway,
1.0% (81).
Focusing more specifically on IGD, a review by Feng et al. (82) of high-
quality papers (n = 27) published from 1998 to 2016 described the prevalence of
IGD-type disorders in naturally occurring convenience samples, which ranged
from 0.7% to 15.7% across studies (however, 15.7% is an outlier by about 6%
due to having used a comparatively low threshold for diagnosis) and averaging
4.7% (82). Although the rate of Internet access had increased exponentially over
15 years in the 29 countries included in the studies, the rate of IGD has remained
stable over the same period. Interestingly, there were not the large variations in
prevalence across countries and regions as had been reported previously (eg, see
ref. (78)). The higher rates of IGD among younger age groups offer the
opportunity for research into primary prevention. A systematic review by Mihara
and Higuchi (83) included 37 cross-sectional and 13 longitudinal studies of IGD
published up to May 2017 and found prevalence rates ranging from 0.7% to
27.5%, with higher prevalence rates in younger populations as well as in males,
but, as did Feng et al., found no geographic differences in prevalence (82). In
most reviews of the prevalence of Internet addiction and of IGD, the differences
in methodologies make it difficult to compare studies and draw conclusions.
Given the large number of IAD definitions and diagnostic assessments as
well as varying prevalence rates by geographical distribution, it is not surprising
that the reported comorbidity of Internet-related disorders and other psychiatric
disorders demonstrates a wide range of prevalence rates in different studies (84).
However, across studies, the prevalence of mental disorders in persons with IAD
is increased compared to populations without IAD. For example, a Turkish
cohort of 10-18-year-olds with IAD (N = 60) was assessed using the Turkish
version of the Schedule for Affective Disorders and Schizophrenia for School-
Age Children and demonstrated that 100% of the students had DSM-IV
psychiatric comorbidity, including 87% with a behavioral disorder (83% ADHD,
23% oppositional defiant disorder, 15% conduct disorder), 72% with an anxiety
disorder (35% social phobia [60% in girls], 23% separation anxiety, 25% OCD),
38% with a mood disorder (30% major depression, 8% dysthymia, 3%
depression OS, 2% bipolar), and 7% with SUD (85). Interestingly, as there are
for SUD comorbidities, there are sex differences as most of the boys (88%) spent
their Internet time in gaming, whereas all of the girls spent Internet time on
social networking sites. This was a treatment-seeking sample and so likely to be
affected by selection bias, and as such, the prevalence rates are probably inflated
over base rates that might be found with an epidemiological survey (85). Wu et
al. (86) recruited a more naturalistic sample of 562 Taiwanese college students
and, using structured interviews (SCID-II), compared the rates of DSM-IV
personality disorders between those with and without IAD, demonstrating higher
overall rates in IAD compared to non-IAD (27.4% vs. 13.9%) and significantly
higher risks in the IAD group of avoidant (25%), borderline (21.9%), dependent
(15.6%), narcissistic (3.1%), or any PD (34.4%) among women and narcissistic
PD (7.3%) among men. Similarly, Zadra et al. (87) also examined the rates of
personality disorders assessed by the SCID-II among a nationally representative
subsample with problematic Internet use (N = 168, ages 20-34 years) extracted
from a large German population-based survey and demonstrated, among those
(N = 71) that met 6 or more criteria for IA derived by substituting the word
“Internet activities” for “gaming” in the DSM-5 IGD criterion set, that 29.6%
with IA and 9.3% not meeting IA criteria had at least 1 PD, significantly higher
in IA for all DSM-IV personality clusters (OR = 1.72), especially Cluster C PD
(anxious/avoidant) among men, supporting the authors’ hypothesis that PD
associated with low self-esteem and high impulsivity might increase the risk of
IA. Despite different countries and age ranges, the prevalence rates of any PD
among those with IA are consistent for the two studies at 27%-30% (86,87).
In order to ascertain a more reliable and valid estimation of relative risks, Ho
et al. (88) conducted a meta-analysis examining the relationship of Internet
addiction and co-occurring other mental disorders from eight studies including
1641 IAD patients and 11,210 controls, which used standardized diagnostic
assessments such as the IAT, the Chen Internet Addiction Scale, etc. and had
sufficient data to generate effect sizes, finding positive associations between
IAD and alcohol use disorder (OR = 3.04), attention deficit hyperactivity
disorder (OR = 2.85), depression (OR = 2.77), and anxiety (OR = 2.70) (88).
Taken all together, as with other use-type disorders, there is an increased risk of
co-occurring mental disorders including personality disorders that, if clinically
unaddressed, would adversely affect treatment outcomes for IAD, IGD, and
other Internet use disorders (89).
INTERNET CHARACTERISTICS
The Internet offers unique characteristics compared to other vehicles with high
liability for unhealthy use and addiction (90), including the following:
Always available: 24/7, lending itself to impulsive access and marathon

sessions
Convenient: No need to leave home or work (those caught downloading
pornography or playing games at work are the tip of the iceberg)
Inexpensive: Internet addiction was more problematic when people were
paying $800 per month of access fees (6). Costs are now much lower now,
making for inexpensive access.
Rewarding: Content rich, with websites consistently present and calculated
to please; increasing, mostly benign interactivity; a continuous flow of new
sites that offer novelty, more videos everyone is talking about, all developed
and distributed at an ever-increasing pace.
Controllable: People can surf the Internet wherever desired and leave at
will. Of course, people with IAD usually feel they can stop at any time.
Using the Internet, a person can better control others’ access to; them but
still interact at a time and place of their choosing.
Escapist: Sites of interest to the potentially addicted offer a welcoming
reality in which all sex partners are attractive and interested and bets are
likely to be won. Some women are attracted to the Internet because they can
act like men (91), whereas introverts can act like extroverts (92).
Validating: One can find something that caters to one’s interests and tastes,
thus verifying that these are legitimate because others feel the same way.
The Internet is always at least nonjudgmental, unless one chooses a role-
playing mode wherein negative feedback is part of the social context but
positive judgments can be found readily.
The Internet may differentially support addictive process as Internet

communication is anonymous and isolated from normative feedback and
provides easy access to reinforcing stimuli. Powerful search engines aggregate
special interest groups and provide virtual and real communities where fringe
behaviors and beliefs are consensually validated (93). Given that some of the
vulnerability to problem use of the Internet is due to the social learning curve
regarding these novel technologies and applications, some of the risks of Internet
addiction might be ameliorated through education and training (94).
TREATMENT MODEL
Theory of Change
Motivation is the key. If rewards are the issue, others must be found. If
obsessive–compulsive concerns are more important, efforts and medication are
directed at developing different habits and thought patterns. Remission is about
learning to avoid triggers for impulsive Internet use, making use of social
support for healthy reinforcers found in everyday life, and relearning how to use
microprocessors in nonpathological ways.
TREATMENT PLANNING
Evaluation—Diagnosis
Internet use disorder is not a DSM-5 diagnosis (1), yet incidence estimates for
Internet addiction range from 1% to 3% of the American population (80). The
addiction field is used to epidemics of powerfully rewarding substances that die
down and become endemic. There seemed to be no end to the crack cocaine
epidemic of the 1970s and 1980s—much was made of rats pressing levers to
inject cocaine into their brains until they died (95)—but it did end. We have had
two decades of concern about unhealthy microprocessor use, and use and
hazardous use are increasing.
The diagnostic divides are among addiction, impulse control (non–
substance-based reward), and compulsive disorders. The addiction field is
familiar with reward mechanisms, dopamine medication, conditioned cues, and
the like. Rewards usually are related to content or specific activities, such as
pornography, gambling, and so on. Diagnoses related to these specific areas are
well established and should be used, although, for example, pathological
gambling had been classified by DSM-IV as an ICD rather than as an addiction
under the substance-related disorder category, where it has now been placed in
the DSM-5 as gambling disorder. There remains a population that compulsively
uses devices without seeming to get much gratification. They do not feel good,
but not doing it leads to feeling bad. Addiction clinicians will recognize this state
of compulsive use that is frequently seen in individuals with addiction to crack
using in spite of the lack of “liking” or individuals with opioid use disorder
injecting heroin in order to “get straight” (negative reinforcement). People who
use devices compulsively rearrange files, check email too often, get on mailing
lists that shower them with trivia, and so on. Frequently, they meet criteria for a
compulsive disorder.
Rating scales serve as diagnostic aids and, in offering objective data for
feedback in motivational approaches, can help patients to realize the extent of
their problems. Several are available but that from the Center for Internet
Addiction Recovery, the IAT
(http://netaddiction.com/resources/internet_addiction_test.htm), is best
established, having been filled out by thousands of visitors to its website (6). Its
20 questions are answered on a 5-point scale (with a sixth alternative: does not
apply). A score of 100 is possible, with ranges of 20-49 indicating average
online use and 50-79 indicating occasional or frequent problems using the
Internet and the “need to assess their full impact on your life.” The questions get
at staying on longer than intended, neglecting household chores, preferring the
excitement of the Internet to intimacy with one’s partner, forming new
relationships on the Web, others complaining about the amount of time one
spends online, decreased productivity (grades, school work, job), checking email
before something else one needs to do, defensiveness or secretiveness when
asked about online activities, blocking out disturbing thoughts about one’s life
with soothing thoughts about the Internet, anticipating going online, thinking life
would be empty and joyless without the Internet, irritability if bothered while
online, losing sleep because of late-night use, preoccupation or fantasies while
offline, rationalizing extra time online, attempts to reduce online time, hiding
how long online, choosing online versus socializing, and depression and
moodiness when offline remedied when online. Many of these items correspond
to similar items in the DSM-IV-TR diagnostic categories of substance abuse and
substance dependence (96). The scale can be used by significant others, who
usually insist on treatment for reasons common to other addiction: a sense of
losing the loved one whose life has been taken over by the addiction, significant
impairment in activities, and relationships, all usually minimized by the patient.
Widyanto and McMurran (75) recruited 86 participants through the Internet who
completed a Web version of the IAT with some added items; factor analysis of
the IAT revealed six factors, which showed good internal consistency and
concurrent validity: salience, excessive use, neglecting work, anticipation, lack
of control, and neglecting social life. More recent meta-analysis of 11 studies
with 6821 participants reveals that the IAT is more reliable in college students
compared to precollege students and has continent-dependent reliability in that
IAT samples from Asia are more reliable than those from Europe (97). A new
scale among many others developed since the publication of DSM-5 (1) in an
attempt to improve and modernize identification of Internet addiction is the
Internet Disorder Scale (IDS-15), a 15-item instrument to assess IA based on a
modification of the nine DSM-5 IGD (98). Psychometric testing among n = 1105
participants demonstrated good construct validity and reliability and provided
capability to attribute low, medium, or high risk for Internet addiction in
individuals based on latent profile analysis statistical techniques (98). Finally,
given the idea discussed earlier that the Internet can provide a vehicle to other,
process-based use disorders, Northrup et al. (99) developed the Internet Process
Addiction Test (IPAT), an exploratory 26-question process addiction screening
tool based on but with a broader symptom set than the IAT, which demonstrated
good convergent, divergent, and concurrent validity and reliability among N =
270 participants, and effectively screened for pathological online Web surfing,
sexual activity, video gaming, and social networking. However, each question of
the 26-item set evaluates seven Internet subprocess domains (eg, surfing,
gaming, sexual, etc.) and is thus too lengthy for typical clinical use.
INDICATIONS FOR TREATMENT

Patients and families understand and feel impairment, so responses to the scale
above and issues of morbidity and mortality can help all concerned understand
indications for treatment.
Mortality
Murder and suicide have been reported after microprocessor deprivation, usually
an adolescent killing the depriving parent or demonstrating through suicide that
life without the microprocessor is not possible. Many of these cases have
occurred in South Korea where the suicide rate, the rate of suicide attempts, and
the use of the Internet and microprocessors are among the highest in the world
(100). One study found that among 452 South Korean adolescents, Internet
addiction identified by the IAT was significantly associated with depressive
symptoms (101). Lee et al. (100) examined cross-sectional data from a very
large school sample of South Korean children in 7th to 12th grade (2008-2010
Korea Youth Risk Behavior Web-based Survey; n = 221,265) and found,
compared to people who used the Internet normally, potential-risk and high-risk
Internet users had increasing risk for both suicidal thoughts (OR = 1.49 and 1.94,
respectively) and past year suicidal behavior (OR = 1.20 and 1.91, respectively)
although a causal attribution is not possible. However, a systematic review
suggested that >5 h of daily Internet use or online gaming is associated with
suicidal ideation and planning, and Internet interactions may inhibit revealing
suicidal thoughts or plans or seeking professional help and may provide
normalizing feedback about self-harm (102).
Morbidity
Morbidity occurs at several levels. The amount of time spent with
microprocessors results in necessary tasks going undone. Real-life social
relationships get less time, and what may be thought to be more satisfying
relationships are developed on the Internet. Impairment can be difficult to tease
out but, as described above, becomes a crucial component of a diagnosis over
and above high engagement. The patient is not necessarily a recluse but can
document that those hours spent in his room involve communicating with
“friends” around the world to play “World of Warcraft.” Objective observers
may rate these relationships less favorably, often reminiscent of a patient with
alcohol use disorder’s drinking buddies. Managing multiple identities can be
taxing, and identity fragmentation occurs if one’s Internet persona is markedly
different from one’s real-life persona. Clinicians have to assess cyber
relationships in detail. Some patients present as having lost touch with what is
the “true” reality. Impairment may also result from physical activity of
prolonged sitting in front of screens, with increased obesity and less exercise.
Decreasing use of national parks, 4 million fewer golfers, and a decline in
outdoor activities may be related to increasing use of microprocessors. However,
inactivity is preferable to accidents that occur while multitasking. The American
College of Emergency Physicians (2008,
http://www.emergencycareforyou.org/YourHealth/InjuryPrevention/Default.aspx?
id=1240) responded to increasing reports of injuries related to being hit or falling
while texting by issuing an alert against “text walking.” It may seem to be
common sense that people should watch where they are walking, but the number
of vehicle hits, falls, and running into trees, lamp posts, and other people has
become noticeable in emergency rooms across the country.
PRETREATMENT ISSUES
Motivation—Rationale for Choice of

Treatment
As with most addiction, motivation prior to engagement in treatment may be
scant or absent. Problems are minimalized, rationalized, or denied. A
nonconfrontational discussion of impairment often helps the patient to gain
perspective. This can be done using the principles of motivational interviewing,
where the facts about the impact of microprocessor overuse are carefully elicited
and then fed back to the patient in a nonjudgmental manner (103). This helps the
patient to use his or her native analytic capacity and values in determining that
the overuse is actually problematic or impairing and helps to tip the decisional
balance toward seeking help to reduce the problem.
An important way station between Internet addiction and returning to the
real world is more therapeutic use of the Internet and microprocessors. This is
somewhat of a departure from the abstinence-oriented approach of classic
addiction treatment. A mother was successful in restricting her daughter’s IM
from 3000 per day to 500 and then 200. Online support groups are thought to
help, but a review of 38 controlled studies of illness (not just Internet addiction)
support groups found no robust evidence of effects, in part because most were
measuring complex interventions (104).
Selection and Preparation of Patients/Suitability

Unlike the subpopulations that comprise the sufferers of many substance
addiction, those with unhealthy microprocessor use are technically competent,
often innovative, and well educated (105), which makes them more suitable as a
group for clinical interventions. However, the subpopulation has been
demonstrated to have high rates of current and lifetime co-occurring mental
disorders, which tend to have a negative impact upon recovery (54). Retreat into
cyberspace may mask co-occurring social phobia and/or other anxiety disorders.
Therapist Characteristics
Familiarity with the Internet and uses of microprocessors and technology is
important for understanding patients, expressing empathy, and earning respect
and credibility with patients, all of which are associated with better treatment
outcomes (106).
Treatment and Technique

Choice and Timing of Interventions
When parents or significant others are in control, taking away or restricting
access to the microprocessor may increase motivation or result in destructive
anger, so clinicians must expect to hear about and perhaps participate in
whatever decision is made. However, similar to binge eating and other disorders
of compulsive food intake, complete abstinence is usually not a feasible long-
term treatment goal, as use of microprocessors is unavoidable in today’s world
and nonuse is associated with significant vocational and social disadvantage.
General and Stage-Specific Interventions

The general plan is reintroduction into the real world, which must be done in
stages to ease transitions. It is a desensitization process, with small steps to be
taken that will bring about a sense of success and increased self-esteem. Where
identity issues predominate, the successful elements of the Internet identity
should be characterized, and there should be an open discussion of integrating
these into the real-world persona. Therapy should be seen as a rewarding process
that helps the patient get in real life what has been available only on the Internet.
This is consistent with community reinforcement principles in replacing the
rewards of the used substance with more natural and socially appropriate
reinforcers (107). With compulsive patients, the therapist can take responsibility
for the compulsive behavior and relieve the patient’s anxiety. Medication
treatment for co-occurring OCD and/or anxiety can be helpful. Clearly, treating
co-occurring mood, anxiety, psychotic, and SUDs is likely to be helpful in
supporting recovery from involvement of significant others and is key to
supporting recovery and reintegration into the real world. Social skills training
may also be helpful.
RELEVANT TREATMENT RESEARCH

Compared to research on psychosocial treatments of SUD, there is far less
relevant treatment research because funding agencies have not yet recognized
the problem as deserving much attention (ie, significant clinical impact, public
outcry, or political will). A survey of clinicaltrials.gov for Internet addiction
reveals one German study of CBT-based treatment for computer gaming
addiction and one nonactive CBT study of IGD and sleep disorders. The
development and use of the Internet are seen as an enormous technological
advance. More and more material is being made available on the Internet, and its
legitimate use is increasing exponentially. There is strong commercial support
for Internet use, as the Internet generates huge advertising revenues and is used
to sell many products. Complaints about Internet addiction can be seen as
spoiling the party. The American Medical Association called in 2007 the
National Institutes of Health and the Centers for Disease Control to start research
programs in Internet addiction, but as of 2017, no federal grant programs have as
yet been announced. As such, much of the available epidemiological and
treatment outcome research devoted to Internet addiction has been based upon
case studies and survey data, of which Internet-based surveys can be driven by
the motivation of the responders and thus subject to selection bias. Given the
increased international attention to IGD, King et al. (108) conducted a
systematic review of 30 studies mostly from China and South Korea of
psychosocial interventions for IGD carried out between 2007 and 2016. The
authors found, using the 25-item CONSORT statement (109), that overall
research quality was impaired due to the disparities in the definition, diagnosis,
and measurement of IGD, the lack of randomized controlled studies with proper
blinding of data acquisition and analysis, and unavailability of recruitment dates,
sample size justification, follow-up reports on changes in gaming or Internet use,
and effect sizes (108). These trends in the design and execution of international
research studies continued despite the 2013 publication of DSM-5 IGD criteria
and a preliminary international consensus for IGD assessment published by
Petry et al. in 2014 (110). There are more than 20 instruments that have been
developed to assess IGD but typically only assessed for 9 of the DSM-5 criteria,
most frequently failing to assess if the patient jeopardized or lost a relationship,
job, or educational or career opportunity (110), but more recent constructs are
fitted to the IGD criterion set (111). Clearly, the research in this area is in need of
standards in assessment and diagnosis with better study design and execution.
Psychologically Based Treatments

Winkler and colleagues conducted a meta-analysis of the extant treatment
research for IAD, including studies with various Internet-related problems, and
found evidence in pre–post analyses for effective treatment of IAD, time spent
online, depression, and anxiety (112). Yeun and Han (113) conducted a meta-
analysis of 37 studies to determine the effect size of prevention-oriented
psychosocial interventions for Internet addiction in mostly South Korean school-
aged children and demonstrated, in spite of considerable variation in diagnostic
approaches and predominantly nonrandomized designs, a large protective effect
on the development of Internet addiction as well as a large effect on self-esteem
and improved self-control. Elements that weighed strongly as variables were
duration of treatment exposure > 10 sessions, CBT, parental involvement in
therapy (for children), and self-control training (113). Yellowlees and Marks
(114) suggest that given that cognitive process maintains IAD, appropriate
psychotherapeutic strategies would include cognitive restructuring focused on
the applications of choice, behavioral exercises, and graded exposure therapy
with increasing duration of offline activity. As such, an early uncontrolled trial
of CBT specifically focused upon Internet addiction demonstrated efficacy in
reducing pathological Internet usage and improving online time management
among 114 patients who were screened with the IAT (105). Young (115)
conducted a more recent noncontrolled study with 128 treatment-seeking
patients screened for IAD with the IAT who were then treated with 12 weekly
sessions of CBT for Internet addiction (CBT-IA), a CBT-based intervention that
initially uses behavior therapy to examine computer and noncomputer behavior
to promote abstinence from problematic sites or applications, moves into
cognitive work to identify maladaptive cognitions that serve as rationalizations
and triggers, and finally works on harm reduction strategies for maintenance of
gains and relapse prevention. Most participants were able to manage their IAD
symptoms effectively by the 12th session and 70% maintained this at 6 months
(115). Similarly, Wölfling et al. (116) treated N = 42 mostly single adult men
with Internet addiction (4/5 with IGD-type problems) with an integrated three-
phase program with 15 group and 8 individual sessions based on CBT and
demonstrated significant reductions in problem severity and negative
consequences of Internet use in this uncontrolled sample (116). In a Chinese
sample, Liu and colleagues conducted a study of manualized 6-session (2 hours)
multifamily group therapy (MFGT) focused on strengthening adolescent–parent
communication and shifting needs fulfillment away from the Internet to real-life
interpersonal interactions, compared to a waiting list control group in N = 42
adolescents and N = 42 parents, demonstrating in the intervention group a
significant reduction in scores on the Adolescent PIU Scale and time spent on
the Internet both at the end of treatment and at 3-month follow-up (117). As yet,
there are no high-quality randomized controlled trials reported for psychosocial
treatment of IAD as a stand-alone construct.
Focusing more specifically on treatment of specific “Internet use disorders,”
there is some evidence from controlled trials suggesting the efficacy of
psychosocial interventions for IGD and Internet-related gambling. Zhang and
colleagues (73) conducted a 6-week study of 40 young Chinese adults with IGD,
comparing a convenience sample of those that received a weekly craving
behavioral intervention (CBI) based on the cognitive behavioral model of Dong
and Potenza (28), and targeting Internet gaming cue-reactive craving (N = 23), to
a matched group that did not (N = 17) and found significant reductions in the
CBI group on visual analogue scale (VAS) measures of cue-induced craving,
durations of weekly gaming, and overall Internet addiction severity (73). Deng et
al. (74) likewise targeted craving behavior in N = 63 Chinese college students
with IGD in a quasiexperimental trial of a 6-session weekly cognitive–
behavioral intervention (including identification of craving triggers and emotion
regulation training, n = 44) compared to a convenience sample (n = 19) waiting
list control group and found significant reductions in severity of IGD, as well as
in VAS measures of current craving for online gaming at postintervention and at
3- and 6-month follow-up (74). The change in self-reported craving accounted
for a significant portion of the effect of the intervention on IGD severity at all
three assessment points, and further analyses revealed that the reduction in
craving was mainly attributable to amelioration in depression symptoms and
shifting fulfillment of psychological needs from the Internet to real-life
interpersonal interactions, suggesting that craving is an important treatment
target in psychosocial treatment of IGD and perhaps other Internet-related
disorders (74). A study combining medications and behavioral intervention
shows promise for CBT for IGD in the context of comorbid mood disorders.
Kim et al. (118) tested 8-session CBT versus no behavioral intervention in
Korean adolescent males (N = 72) with major depression and IGD-type Internet
addiction (based on DSM-IV substance abuse criteria) who were treated with
bupropion and demonstrated significant reductions in online gaming time and
Internet addiction severity in the CBT group at study end and at 4-week follow-
up, as well as a significant reduction in depression severity compared to controls.
Cognitive–behavioral-based interventions may also have applicability in
treating Internet gambling disorder. With Internet-based behavioral addiction, it
is unclear as to whether a focus on reducing pathological Internet use or more
specific targeting of the substrate will have more clinical efficacy. Petry and
Gonzalez-Ibanez (120) conducted a secondary analysis of results from a primary
study of brief interventions for problem gambling (119) where for this analysis
the data from the three active intervention groups (10-15’ brief advice, 50’
motivational enhancement therapy (MET), and MET + 3 additional CBT
sessions) were combined and compared to the control group (assessment only) in
mostly male (>80%) college students with (N = 57) or without (N = 60) recent
Internet gambling (120). Although at baseline the recent Internet gamblers
gambled more frequently and with higher stakes and had significantly more
anxiety and interpersonal and school impairment than did the non-Internet
gamblers, the impact of the three active interventions compared to controls in
significantly reducing gambling behavior over time was not different between
groups, suggesting that Internet-based gambling disorders are responsive to brief
therapies focused on gambling behavior rather than Internet behavior per se
(120). In contrast, Luquiens et al. (121) screened with a survey and recruited
non–treatment-seeking problem Internet gamblers on a poker website for a 6-
week randomized clinical trial of three brief interventions targeting gambling
behavior, emailed automated personalized feedback from individual survey
scores, an emailed self-help book with an unguided CBT program, and a CBT
program emailed weekly with professional guidance, versus a waiting list
control group, and found that in all groups, the dropout rate was high, but study
completers had significantly reduced gambling severity scores. However, the
group that received the professionally guided CBT had the highest dropout rate,
suggesting that CBT-type interventions may not be appropriate in Internet
gamblers who are not treatment seeking (121).
Pharmacotherapy and Psychologically Based

Treatments
Regarding pharmacotherapy for IAD, one study reported therapeutic success
with escitalopram, a selective serotonin reuptake inhibitor antidepressant (122);
however, the active treatment phase was open label. Han et al. (123) treated
males (n = 11) addicted to Internet video gaming with sustained-release
bupropion titrated to 300 mg/d over a 6-week period and compared them to
healthy controls who had the same video game preference as the experimental
group, but not pathologically. Not only were the total amount of time spent
playing, related maladaptive behaviors, and video game craving reduced at 6
weeks and significantly correlated with the drop in time spent playing, but video
cue-induced brain activity in the dorsolateral prefrontal cortex, as assessed by
fMRI, was also reduced from baseline (123). An 8-week trial of methylphenidate
for ADHD (mean dose 30.5 mg/d) in Korean children (n = 62) examined the
impact on measures of Internet addiction and Internet usage as well as ADHD
symptoms and visual continuous performance test function and demonstrated
reduced inattention and impulsivity–hyperactivity scores, as expected, as well as
significantly reduced scores on hours of Internet use and the Internet Addiction
Scale, which was significantly correlated with the decrease in ADHD symptoms
(124). Additionally, a single case study reported, after failure of multiple
antidepressant trials as well as psychosocial and self-help approaches, successful
treatment of Internet-based sex addiction with up to 150 mg/d of oral naltrexone
when added to a baseline of sertraline 100 mg/d, which supported normalized
social, occupational, and personal function (125). Finally, Han and Renshaw
(126) conducted an 8-week randomized trial of bupropion SR 300 mg/d plus
weekly education for problematic Internet use compared to weekly education
alone in male patients (N = 50, 13-45 years old) with DSM-IV major depression
and severe problem Internet gaming and demonstrated that in addition to
significantly reduced depression severity in the medication group there was
significantly reduced severity of Internet addiction as well as mean online game
playing time. Interestingly, in the prospective case series of recruited and
treatment-seeking pathological Internet subjects described above, there were
high rates of current comorbid bipolar depression that responded to
anticonvulsant treatment (with or without adjunctive antipsychotic or
antidepressant agents) with both normalization of mood and moderate to marked
remittance of pathological Internet use (54). However, it is important to note that
if IAD follows suit with chemical addiction, then effective treatment of co-
occurring other mental disorders will generally have effect sizes insufficient to
treat the IAD (127).
SUMMARY AND CONCLUSIONS

Use of microprocessors continues to increase rapidly as these are placed in a
wide variety of communication and amusement devices. These devices are
always available, cost little to use, and provide many rewards. About 1% of the
US population has unhealthy microprocessor use. These problems are likely to
increase as microprocessor use and power continue to increase. While sharing
many commonalities with other addiction, unhealthy microprocessor use differs
in that no exogenous substance is involved and patients are technologically
savvy and computer literate and are able to manipulate their identities in
cyberspace.
Even without resorting to a pathology model, current societal adaptation to
the use of microprocessors can, at its most extreme, be likened to the London gin
epidemic, where citizens previously comfortable with a culture that drank beer
and ale, frequently to intoxication, had to adapt poorly to a new more potent
alcoholic liquid, with disastrous results in a population that was already ripe for
social unrest (128). Eventually, the culture moderated its use more globally,
leaving the bulk of maladaptive and damaging alcohol-related trajectories to
those with alcohol use disorders. It may be that our culture is on a similar path
and in the wake of our corporate learning curve will be those for whom
microprocessors provide a “substance” fulfilling its role as a substrate for a
pathological use disorder (3,54,80,125,129–131).
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CHAPTER 48
Behavioral Syndromes to Consider as
Forms of “Addiction”
Abigail J. Herron, Paul J. Rinaldi and Petros Levounis
CHAPTER OUTLINE
Introduction
Compulsive Buying Disorder
Excessive Tanning
Kleptomania
Shared Features of Behavioral and Substance Addictions
Co-Occurrence of substance use and Behavioral Addictions
Diagnostic Challenges
Treatment Models
Conclusion
INTRODUCTION
Three primary components have been described as the core elements of
addiction: craving or compulsion, loss of control, and continued behavior despite
associated negative consequences (1). While the term addiction has been often
used to exclusively describe impaired control over substance use (2,3), these
core elements can be seen in certain behaviors associated with short-term
rewards that lead to persistent behavior despite adverse consequences. This
shared feature of diminished control has given rise to the concept of behavioral
addictions, syndromes similar to substance addiction (generally referred to as
substance use disorders), but with a behavior as the core of the disorder rather
than a substance (4,5).
Traditionally, these behaviors have been classified as impulse-control
disorders (ICDs). The Diagnostic and Statistical Diagnostic Manual of Mental
Disorders, 5th ed. (DSM-5) expanded this category to “Disruptive, Impulse-
Control, and Conduct Disorders,” which include oppositional defiant disorder,
intermittent explosive disorder, conduct disorder, antisocial personality disorder,
pyromania, kleptomania, and other specified and unspecified disruptive,
impulse-control, and conduct disorders (6). Several other disorders have been
proposed for formal recognition as ICDs, including compulsive shopping,
problematic Internet/computer use, compulsive sexual behavior, compulsive skin
picking, and compulsive tanning (7,8). Defining characteristics of these
disorders include repetitive or compulsive engagement in a specific behavior
despite adverse consequences, diminished control over the problematic behavior,
and tension or an appetitive urge state prior to engagement in the behavior (7).
While many of these disorders share features with substance use disorders,
others do not. The shared characteristics of some behavioral disorders and
substance use disorders have raised the question of whether they would more
appropriately be classified as addictive disorders.
In this chapter, we will discuss shared features of behavioral and substance
addictions, co-occurrence, diagnostic challenges, and treatment options. Several
of the behavioral disorders are covered in depth in other chapters in this text, but
we will include three of them here—compulsive buying disorder (CBD),
excessive tanning, and kleptomania—as specific examples of conditions that
may merit reclassification as substance use disorders. We have chosen to include
these disorders because they are activities that can be considered pleasurable,
exciting, and naturally rewarding at normative levels, similar to that of substance
use. Others, such as skin picking or trichotillomania, are pathological even at
lower levels of activity and seem to be better classified as obsessive–compulsive
disorder (OCD) spectrum disorders. When the behaviors that result in such
pleasurable rewards cross to the pathological level, they may be considered
addictions.
COMPULSIVE BUYING DISORDER

Compulsive buying was first described by Kraepelin (9), who wrote about
oniomania, which is uncontrolled shopping and spending. Bleuler (10) described
“buying mania” as an example of a reactive impulse or impulsive insanity. He
categorized it along with pyromania and kleptomania. Although compulsive
buying is not specifically described in the DSM-5, diagnostic criteria have been
proposed. These include being frequently preoccupied with buying or subject to
irresistible, intrusive, and/or senseless impulses to buy; frequently buying
unneeded items or more than can be afforded; shopping for periods longer than
intended; and experiencing adverse consequences, such as marked distress,
impaired social or occupational functioning, and/or financial problems. There
has long been debate about whether this is a true disorder. It was included in the
DSM-III but was excluded from the DSM-IV and DSM-IV-TR. In the DSM-III-R,
it was included as an “impulse-control disorder not otherwise specified.” While
there has been debate about the classification of the disorder, it is widely
accepted by clinicians that it is a serious condition requiring intervention.
The estimated prevalence of CBD in the United States is ~5.8% (11).
Prevalence rates in the literature have been as low as 1.8% (12) and as high as
8% (13). The usual age of onset for CBD appears to be in the late teens to early
20s (14). Most subjects identified are female, but a study by Koran et al. (11)
that used a large general population sample found that the prevalence of CBD
between women and men was only slightly different.
McElroy et al. (16) found extremely high comorbidity rates among people
with CBD. She found that compulsive shopping behavior might be related to
mood disorders, OCD, or ICD. Male compulsive buyers were more likely to be
diagnosed with “sexual addiction” and intermittent explosive disorder (15).
First-degree relatives of people with CBD are more likely to have psychiatric
disorders such as alcohol or substance use, major depression, and anxiety
disorders than first-degree relatives of people without CBD (16,17). Black (18)
identified four phases, which are anticipation, preparation, shopping, and
spending. In the first phase, the person becomes preoccupied with either
purchasing a specific item or shopping in general. In the next phase, the person
plans the purchase or shopping spree. This is followed by the actual shopping
experience during which many of those with CBD feel intense excitement. The
actual purchase completes the cycle. Following the purchase, the person often
experiences feelings of disappointment, shame, or guilt.
Similar to kleptomania, neurobiological theories have focused on disturbed
serotonergic, dopaminergic, or opioid neurotransmission. Some argue that CBD
should be included in the nosological classification as an substance use disorder.
The reasoning is that some ICDs share features in common with substance use
disorders: comorbidities, family histories, and brain circuitry. There is evidence
that the brain circuitry in substance use disorders, namely, the “reward system”
of the brain, is involved in ICDs (5).
There are no definitive evidence-based treatments for CBD (19). Treatments
have generally followed the same protocols as with other ICDs, namely,
cognitive–behavioral therapy (CBT) and pharmacotherapies. Pharmacotherapies
have included the use of SSRIs, particularly fluoxetine and citalopram. Grant et
al. (20) have shown some improvements with naltrexone, suggesting that opioid
antagonists might play a role in CBD. Since the medication findings are mixed,
no empirically supported treatment recommendations can be made. CBT has also
been recommended. Most of the CBTs that have been developed involve group
therapy. Mitchell et al. (21) found that group CBT yielded significant
improvement compared to a control group and that the improvements attributed
to CBT were maintained during a 6-month follow-up.
Since CBD occurs mostly in developed countries, sociocultural factors have
been proposed either as etiological agents or to promote the disorder. Neuner et
al. (22) reported an increase in the frequency of CBD in Germany following
reunification. This led to the conclusion that societal factors can contribute to the
development of CBD. These factors can include the availability of goods, easily
obtained credit, a market-based economy, and disposable income.
Available empirical evidence is insufficient to draw conclusions about
whether CBD exists as a distinct disorder or whether it is a subtype of other
disorders. While many clinicians agree that the people suffer from this disorder,
randomized clinical trials are needed in order to definitively study and classify
CBD.
EXCESSIVE TANNING
According to an 8th-century Japanese proverb, “white skin makes up for seven
defects” (23). For many centuries, fair skin was celebrated as a sign of beauty
and elegance in Western and Asian cultures. It was not until the early part of the
20th century that tanning was introduced as a desirable trait when Coco Chanel
famously declared, “The 1929 girl must be tanned. A golden tan is the index of
chic!” and, suddenly, pale became passé (24). Since then, the Western world has
idolized darker skin and tanning, and only recently, we have started to question
this model.
In the 21st century, there is little doubt that sun exposure causes skin cancer.
Whether people suntan naturally or use indoor tanning sunbeds, the risk of
developing cancer has been well established (25). In response to this serious
public health concern, both the government and the media have made significant
efforts to educate the public, raise awareness, and promote the use of sunscreens
with high sun protection factor. The result is that the new millennium has now
developed a highly ambivalent relationship with the sun and its surrogates, the
tanning lamps.
This widespread ambivalent relationship notwithstanding, there is a
subgroup of people for whom tanning is clearly excessive and seems to reflect
frank psychopathology. Excessive tanning is not recognized in the DSM-5
diagnosis, nor is it mentioned as an example of an unspecified ICD. However,
for this subgroup of people who tan excessively, their presentation,
symptomatology, psychiatric comorbidity, consequences of behavior, and overall
course of illness resemble significantly the trajectories of other behavioral
addictions and the substance use disorders. Kaur et al. (26) reported on a small
study of regular sunbathers who exhibited opioid-like withdrawal symptoms
upon administration of naltrexone, an opioid antagonist.
In 2005, Warthan et al. (27) published a seminal article in the Archives of
Dermatology with the title “UV light tanning as a type of substance-related
disorder.” They interviewed 145 beachgoers using a modified CAGE
questionnaire (28), a common screening instrument for unhealthy alcohol use,
and found that approximately one in four participants met the criteria for a
tanning-based, substance-related disorder. The article was provocative at the
time and several addiction experts denounced its findings as disrespectful to
people who suffer from “true” addictions like the substance use disorders (29).
Since then, we have come to appreciate excessive tanning as a candidate for
consideration as a behavioral addiction.
While most recent research has adopted the addiction paradigm in
understanding excessive tanning, there are other psychiatric disorders that may
also explain the manifestations of the illness. Sansone and Sansone (30)
proposed the following three disorders as “possible underlying
psychopathologies” for excessive tanning: OCD, body dysmorphic disorder
(BDD), and borderline personality disorder (BPD).
At this time, limited research has been conducted to support or refute these
explanations. Furthermore, an alternative formulation of the illness could
suggest that excessive tanning may be a behavioral addiction that is often found
to be comorbid with these disorders—OCD, BDD, and BPD. We have not
encountered any clinical or epidemiological studies that could shed some light
into these alternatives.
The lack of research in this area extends to treatments. However, if we
accept that excessive tanning is best appreciated as a behavioral addiction, then
(a) addressing underlying or co-occurring psychiatric conditions and (b)
providing CBT or motivational interviewing (MI) seem to be the most
reasonable approach to treatment. A small three-group randomized clinical trial
by Turrisi et al. (31) demonstrated that young women who frequently used
indoor tanning facilities markedly reduced their tanning events following a one-
on-one MI session using a personalized graphic feedback delivered by a trained
peer counselor. Comparison groups that were provided with identical graphic
feedback but through the Internet with no person-to-person or no intervention
did not demonstrate any change in tanning events.
A number of other psychosocial interventions have been tried in small
samples of more normative populations, including the following three, which
have shown some promising results:
Showing patients ultraviolet photos of skin damage (32)

Showing patients “image norms of aspirational peers” (e.g., media figures
and fashion models) approving paleness (33)
Providing feedback on the patient’s suntanning behavioral patterns by a
physician (34)
In addition to treatments, prevention has to play a major role in addressing the

proposed illness, especially since there is little evidence of safe and effective
therapeutic interventions. Current public heath efforts go beyond raising
awareness of the risk of excessive sun exposure. State, federal, and international
regulations are being considered and implemented to limit indoor tanning by
imposing higher taxes and prohibiting minors from using such facilities (35). At
least 44 states and the District of Columbia regulate indoor tanning for minors.
Sixteen states and one territory ban the use of ultraviolet tanning devices by
anyone under age 18 (36).
KLEPTOMANIA
The DSM-5 (6) includes kleptomania as a distinct diagnosis in the category of
disruptive, impulse-control, and conduct disorders. The following symptoms are
recommended for a diagnosis of kleptomania:
Repeated inability to defend against urges to steal things that are not
essential for private use or for their economic value.
Escalating sense of pressure immediately prior to performing the theft.
Satisfaction, fulfillment, or relief at the point of performing the theft.
The theft is not executed to convey antagonism or revenge and is not in
reaction to a delusion or a fantasy.
The theft is not better accounted for by behavior disorder, a manic episode,
or antisocial personality disorder.
Kleptomania is characterized by recurrent episodes of compulsive stealing.

Often confused with shoplifting, it differs in that those with kleptomania do not
steal for personal gain. They steal in response to an overwhelming urge that they
are unable to resist. The powerful urge causes feelings of anxiety, tension, or
arousal. Stealing soothes these feelings. However, following this, there are often
feelings of guilt, remorse, and fear. These feelings frequently serve as barriers to
treatment seeking.
The discussion of kleptomania in the 19th and early 20th centuries became
part of the ongoing debate in the medical community about the relationship of
insanity to the female reproductive system. Because most shoplifters at the time
appeared to be women, this link was made. “Hysteria” was thought to be caused
by the uterus, so kleptomania was discussed along with other diseases of the
female reproductive organs. By 1920, the labeling of certain shoplifters as
kleptomaniacs largely disappeared. It is unclear why this occurred but might
have been connected to the fact that no one in the scientific community was able
to prove that female reproductive issues caused shoplifting and more men were
being arrested for shoplifting.
Although the DSM-5 lists kleptomania as an ICD, there is emerging
evidence that suggests similarities between kleptomania and substance use
disorder and mood disorders. Kleptomania is a psychiatric disorder that is poorly
understood and subject of only a few empirical studies (37). While the
prevalence of the disorder in the US general population is unknown, it has been
estimated at 6 per 1000 people (37).
It is classified as an ICD since the behavior cannot be explained by antisocial
personality disorder, conduct disorder, or a manic episode, and it involves the
inability to control ones impulse to steal. A core feature of ICDs is the repeated
expression of impulsive acts that lead to physical or financial damage to the
individual or another person.
While kleptomania meets criteria for ICD, it shares many characteristics of
OCD. Grant and Potenza (8) state that there is emerging evidence derived from
studies of clinical characteristics, familial transmission, and treatment response
that suggests that kleptomania may have subtypes that are more like OCD,
substance use disorder, or mood disorders.
A correlational aspect linking kleptomania to OCD is seen in the biological
perspective on OCD. Studies of the brain using magnetic resonance imaging
showed that subjects with OCD have significantly less white matter than did
normal control subjects, suggesting a widely distributed brain abnormality
associated with OCD (38). OCD is considered a result of serotonin deficiency.
SSRIs have been used to treat both OCD and kleptomania and have been
considered a link between the disorders.
Prevalence rates between the two disorders do not show a strong
relationship. The results of studies that examined the comorbidity of OCD in
subjects with kleptomania have been inconsistent with some showing a relatively
high co-occurrence (45%-60%) while others showing low rates (0%-6.5%).
When rates of kleptomania have been examined in subjects with OCD, a
similarly low co-occurrence was found (2.2%-5.9%) (39).
A connection between depression and kleptomania was reported as early as
1911. There is strong anecdotal evidence of such in case reporting. Some people
report feelings of relief of depressed mood or manic symptoms after theft.
Recent studies have not found that people with kleptomania are more likely than
others to have major depression or bipolar disorder.
Kleptomania and substance use disorders have central qualities in common.
These include recurring or compulsive participation in a behavior in spite of
undesirable consequences, weakened control over the disturbing behavior, an
overwhelming need or desire experienced before taking part of the problematic
behavior, and a positive pleasure-seeking condition throughout the act of the
disturbing behavior. The anxiety, tension, or arousal that those with kleptomania
experience and the relief that they feel upon stealing, followed by guilt or
remorse, are consistent with opponent process descriptions (40) and wanting-
but-not-liking states (41) described for substance use disorders. Similar to
substance use disorders, a higher percentage of cases of kleptomania have been
noted in adolescents and young adults, and a smaller number of cases among
older adults. Family history data also show a likely common genetic input to
substance use and kleptomania. Substance use disorders are more common in the
family members of persons with kleptomania than in the general population.
Treatment for kleptomania has many commonalities with treatment for
substance use disorders and OCD. Treatment usually consists of a combination
of therapies including pharmacotherapy and psychotherapy. While there are no
medications specifically approved for the treatment of kleptomania, the
similarity and suggested biological dynamics of kleptomania and OCD and ICDs
led to the theory that similar groups of medications could be used for all of these
conditions. Fluoxetine and other SSRIs have been widely used to treat
kleptomania; however, there has not been strong evidence supporting the
efficacy of SSRIs in treating the disorder. There has been some promising
evidence supporting the use of mood stabilizers, antiseizure medications, and
opioid antagonists, particularly naltrexone. Opioid receptor antagonists have
been shown to lessen urge-related symptoms, which are a central part of ICDs
and substance use disorder (42). In the past, psychoanalytic and dynamic
approaches were used to treat kleptomania. Current practice usually includes
CBT. CBT can include covert sensitization, exposure and response prevention,
and imaginal desensitization (42).
SHARED FEATURES OF BEHAVIORAL

AND SUBSTANCE ADDICTIONS
Behavioral disorders resemble substance addictions in a number of domains
(43). Individuals with behavioral and substance addictions demonstrate high
levels of self-reported impulsivity and sensation seeking (44). They have similar
natural histories, with increased prevalence in adolescents and young adults (45),
chronic relapsing patterns, and the possibility of spontaneous recovery.
Gambling disorder, the most studied of the behavioral addictions, mirrors
substance use disorders with higher rates seen in men. A telescoping pattern is
seen in women, with later initiation of behavior, but with shortened period from
initial behavior to addiction (46,47). Interpersonal conflicts are seen in both
behavioral addictions and substance use disorders. The financial problems
common to both can lead to illegal acts such as theft or forgery to offset the
consequences of the behavior (48). Neurobiological and genetic parallels have
also been shown between substance use disorders and ICDs, with implications
for the role of the dopamine and serotonin neurotransmitter systems (49,50).
In both types of addiction, behavior is often preceded by an urge or craving.
Emotional dysregulation may contribute to cravings, and the resultant behavior
can often decrease anxiety and lead to a positive mood or “high” (51). Many
individuals report a decrease in these positive effects over time or a need to
increase the intensity of their behavior in order to achieve the same effect,
analogous to tolerance seen with substance use (52,53). In periods of abstinence
from these behaviors, a dysphoric state may also be seen, analogous to
withdrawal, although with no prominent medical symptoms, which does differ
from withdrawal from substances. While these behaviors are initially ego-
syntonic, they may become more ego-dystonic over time as the act becomes less
pleasurable and more motivated by negative reinforcement (41,50).
CO-OCCURRENCE OF SUBSTANCE USE

AND BEHAVIORAL ADDICTIONS
There are limited data from large national studies as to co-occurrence of
substance use disorders and behavioral disorders. ICDs have not been measured
in most large-scale epidemiological surveys (5), in part because validated
instruments for the assessment of these disorders are largely lacking. Studies of
clinical samples, however, suggest high rates of co-occurrence, most notably
between gambling disorder and substance use disorders (54–56). Clinical
samples of other behavioral addictions suggest that co-occurrence of a substance
use disorder is common, with rates of substance use disorders 22%-50% in
kleptomania and ~60% in compulsive sexual behavior (57). In a study of 1600
adolescents, Chuang et al. (58) found that adolescents who endorsed either
impulsivity or at least two behavioral addictions alone were more likely to have
used tobacco, alcohol, or marijuana. Additionally, among those who had never
tried a drug, individuals with this combined set of risk factors were the most
likely to be susceptible to future drug use.
High comorbidity may suggest that these disorders are part of the same
spectrum and should be classified together as substance use disorder. Yet,
individuals with behavioral disorders have also been shown to have higher rates
of other psychiatric disorders, including mood, anxiety, and personality
disorders, which are not part of the addictive process (55). Causal relationships
may be behavioral (e.g., substance use disinhibits other inappropriate behaviors)
or syndromal (e.g., behavioral addiction begins during abstinence from
substance use as a substitute activity) (59). Psychiatric comorbidity alone does
not lend support for the classification of these disorders as addictive. This does
highlight, however, that individuals with substance use disorders should be
assessed for the presence of ICDs.
DIAGNOSTIC CHALLENGES
Historically, behavioral addictions have not shared formal diagnostic recognition
with substance addictions. In the DSM-IV-TR, the term addiction was not
included in the nomenclature (60), a distinction that was carried through into
DSM-5 as well. Substance use disorders are classified by specific substance and
described by related conditions (i.e., intoxication, withdrawal, etc.). Of the
proposed behavioral addictions described above, only gambling disorder is
recognized as a formal substance use disorder in the DSM-5. The diagnostic
criteria are similar to those for substance use disorders, including preoccupation
with the behavior, diminished control, tolerance, withdrawal, and negative
consequences.
Data about many of the ICDs are lacking, and more evidence is needed to
aid in the classification of these disorders. Empirically validated instruments for
assessment of ICDs would allow for identification of behavioral disorders in
large-scale epidemiological studies, and longitudinal assessment would be useful
in mapping the temporal relationships between ICDs and other psychiatric and
substance use disorders (5). Brief screening instruments would be helpful in the
identification of ICDs in both clinical and research populations.
Changes to the DSM-5 include the development of a category termed
“Substance-Related and Addictive Disorders,” which includes a diagnosis of
gambling disorder (6). Additionally, Internet use disorder has been suggested as
a condition for further study. Support for use of the term “addiction” rather than
the current term “dependence” has centered on confusion over different
definitions of dependence. Physical dependence can occur following chronic
administration of a substance and feature tolerance and withdrawal, without the
experience of the negative consequences of addiction. A change in terminology
may allow the focus to shift from substance use and its adaptation-associated
physical consequences to the harmful effects of addiction on multiple domains of
functioning.
There are a number of advantages associated with categorizing certain ICDs
as substance use disorders. Rates of co-occurrence are high, there are common
demographic and epidemiological features, and there are parallels between
presenting symptomatology. Substance use treatment programs may be more
likely to assess for the presence of ICDs in their patient population than general
mental health or primary care settings. By expanding the scope of addiction to
include these disorders, it may increase awareness, extend treatment for these
conditions in the context of substance use treatment, and increase the availability
of funding and research into these disorders (59).
Despite the advantages described above, several disadvantages to
reclassification exist. The primary rationale for the separate classification has
been the lack of substance use with the ICDs, resulting in distinct consequences
from use, particularly regarding the lack of significant physical sequelae from
ICDs. Additionally, categorizing ICDs as addictive may increase stigmatization.
Individuals without co-occurring substance addiction may feel uncomfortable
receiving treatment in a substance use treatment setting. Treatment programs that
primarily treat substance use may not have a sufficient number of patients with
ICDs to offer groups dedicated to their treatment (59).
TREATMENT MODELS
Behavioral and substance addictions can respond positively to the same
treatments modalities. While research continues in this area, there are no
currently approved medications for the treatment of behavioral addictions.
Psychosocial therapies play many roles in the treatment of co-occurring
substance and behavioral addictions. They are used to directly target and reduce
problem behaviors in both domains directly as well as indirectly through the
rationale that reductions in one type of behavior are likely to lead to reduced
symptom severity and reductions in other problematic behavior. Behavioral
therapies can also be used to enhance treatment engagement and promote
treatment adherence and can target other psychosocial problems that may occur.
Multiple psychosocial approaches have been employed in this treatment.
Many treatments for behavioral addictions were originally developed for the
treatment of substance use disorders, and psychosocial treatments for both types
of disorders often employ a relapse prevention model, encouraging abstinence
through identification of patterns of use, avoidance or coping mechanisms for
high-risk situations, and lifestyle changes (61). CBT, motivational approaches,
and 12-step approaches are mainstays of substance use treatment that have been
successfully used in the treatment of a number of ICDs, including gambling
disorder, compulsive sexual behavior, kleptomania, pathological skin picking,
and compulsive buying (21,62–64). CBT focuses on learning new skills and
strategies to reduce negative thoughts and behaviors, helping individuals to
identify patterns associated with ongoing substance use or other behaviors.
Motivational approaches are brief interventions designed to produce internally
motivated change in problematic behaviors. Contingency management, in which
individuals receive incentives or rewards for demonstrating observable target
behaviors (such as negative urine toxicology or treatment attendance), has been
shown to be effective in reducing substance use (65) and may be similarly
effective when used for reducing other problematic behaviors.
There is a large body of evidence demonstrating high rates of comorbidity
between substance use disorders and other mental health disorders (66–69),
which stresses the treatment delivery system. Individuals with co-occurring
disorders have also been shown to have poorer treatment outcomes, highlighting
the need for effective treatment models to address co-occurring disorders.
Several options exist for the delivery of care to the patient with co-occurring
substance and behavioral addiction, including deferred treatment, serial
treatment, parallel/concurrent treatment, and integrated treatment. Integrated
treatment, in which interventions and services are directed at both disorders by
the same treatment team at the same time, is now recommended as the standard
of care for substance use and mental health disorders (68) and may also be the
preferred model for co-occurring behavioral addiction and substance use
disorders.
Integrated treatment offers a number of advantages. Individuals receive
combined treatment for behavioral and substance addiction from the same
treatment team, allowing for a deeper treatment alliance, a unified treatment
philosophy, and ongoing communication among providers. It also increases
access to treatment by allowing individuals to receive treatment at a single
facility. Integration of services is essential for individuals with significant
impairment in both domains and for those whose treatment for one type of
disorder is negatively impacted by the presence of the other disorder.
There are challenges to this approach as well. Individuals may be in different
stages of change and different phases of treatment for different disorders,
necessitating distinct treatment interventions for each disorder. Given the
heterogeneity of behavioral addictions, there are challenges to maintaining
adequately trained staff. The increased cost of training staff to provide these
interventions may be a barrier to implementation. There are few centers that
specialize in the treatment of behavioral addictions, so these interventions are
often delivered by programs that primarily treat substance use. It may be difficult
to gather a sufficient number of patients with behavior disorders in order to offer
groups dedicated to their treatment.
CONCLUSION
Evidence suggests parallels between substance and behavioral addictions in
many domains, including epidemiology, natural history, symptomatology, and
comorbidity. The data lend support but still require more study toward
consideration of compulsive buying disorder, excessive tanning, and
kleptomania as representative of addiction disorders, and moving their
categorization (as was done with gambling disorder in DSM-5) into the DSM’s
future version of “substance-related and substance use disorders.” While
controversy remains concerning the nomenclature, these shared features have
treatment implications, with a number of behavior disorders responding
positively to modalities initially employed in the treatment of substance use
disorders. Further study is needed to fully understand the etiology of these
behavioral disorders, optimize behavioral and pharmacological treatments, and
develop prevention strategies.
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CHAPTER 49
Physician Health Programs and
Addiction Among Physicians
Paul H. Earley
CHAPTER OUTLINE
Introduction
Prevalence
Characteristics of Physicians with Addiction
Drugs Used
Risk Factors
Addiction Comorbidity
Theories of Addiction Among Physicians
Identification, Intervention, and Assessment
Treatment
Controversies
Conclusion
INTRODUCTION
The available research about addiction among physicians and physician health
programs (PHPs) is extensive and has been well documented in several excellent
overviews (1–10). Bissell and Haberman (11), Angres et al. (12), Nace (13), and
Coombs (14) have written complete texts about addiction in physicians and other
health professionals. Physicians are a convenient population to study; they are
accessible both prior to and after treatment and are articulate about their disease.
Research on physician addiction elucidates the natural course of addiction in a
highly regulated and monitored population. At the same time, physicians differ
from the general population in terms of education, income, and regulatory
oversight; therefore, conclusions about the efficacy of addiction treatment
among physician–patients cannot simply be generalized to the population at
large. However, the highly structured and consistent treatment model developed
for the care of this population does provide clues for treatment improvement
with all populations. Less research is available about other health professionals;
however, many of the issues and concepts described here may prove helpful for
all healthcare workers as well as safety-sensitive workers in general.
PREVALENCE
We have 20 years of debate about the actual and changing prevalence of
addiction among physicians (7). Kessler et al. (15) reported that 3.8% of the
general population at any given time has any substance use disorder and 1.3%
meets criteria for pre–DSM5-defined alcohol dependence and 0.4% for drug
dependence. Lifetime prevalence for alcohol use disorders has been estimated at
between 8% and 13% in the general population. Prevalence studies among
physicians report widely varying rates dependent upon research methodology
(7,16–21). Hughes et al. (20) reported a lifetime prevalence of alcohol abuse or
dependence and drug abuse or dependence in physicians at 7.9%, somewhat less
than the percentage reported in the general population by Kessler et al. (15).
However, methodologic differences may account for the observed differences.
The Hughes study surveyed 9600 physicians by mail with a lower response rate
(59%) and relied on honest and denial-free reports by the physician self-report;
the Kessler general population study utilized face-to-face interviews with trained
interviewers.
Vaillant et al. (22) reported on the types of substances physicians use in the
1960s. At that time, he noted that physicians were just as likely to smoke
cigarettes and drink alcohol as the general population but more likely to take
tranquilizers and sedatives. In a more comprehensive study 29 years later,
Hughes et al. (18) noted that physicians were less likely to smoke cigarettes than
were nonphysicians and more likely to consume benzodiazepines and opioids.
This shift is striking; Mangus et al. reported in 1998 that 2% of graduating
students smoked (23); a second 2002 study reported that 3.3% of medical
students smoked cigarettes (24).
In 1992, Hughes et al. (20) reported that physicians are more likely to drink
alcohol than the general population; the authors attributed this in part to their
higher socioeconomic status. They also noted that 11.4% of physicians had used
unsupervised benzodiazepines and 17.6% reported the unsupervised use of
opioids. Vaillant (25), in his commentary on the Hughes study, rang an alarm
bell by stating “physicians are five times as likely [as the general population] to
take sedatives and minor tranquilizers without medical supervision.” The use of
opioids and minor tranquilizers commonly begins prior to or in medical school,
since medical students are more likely to use these drugs than age-matched
cohorts (26). Clark examined substance use in medical students using a 4-year
longitudinal study (27). Eighteen percent met the study’s criteria for unhealthy
alcohol use in the first 2 years of medical school. They reported that a family
history of alcoholism was associated with unhealthy alcohol use in the medical
student. Another view of physician unhealthy use of alcohol and drugs can be
derived from complaints reviewed by state medical boards. Morrison and
Wickersham (28) noted that 14% of board disciplinary actions were alcohol or
drug related and another 11% were due to inappropriate prescribing practices—
many of which are also addiction related. In 2003, Clay and Conatser (29)
reported similar disciplinary rates, with 21% due to alcohol and drug issues and
10% due to inappropriate prescribing or drug possession.
Alcohol- and drug-related work impairment was the primary impetus for the
formation of state PHPs in the United States and continues to account for the
majority of physician impairment cases seen by most PHPs today (30). David
Canavan, MD, started the first PHP (New Jersey) in 1982. Since that time, “all
but three of the 54 US medical societies of all states and jurisdictions had
authorized or implemented impaired physician programs” (31). The most recent
PHP (Georgia) opened its doors in 2012. In 2008, California moved against this
trend by dissolving its PHP, joining Delaware, Nebraska, and Wisconsin as one
of the few states without a PHP (32). Please see the sidebar—The California
Diversion Program: A Cautionary Tale.
Ethnic variation in substance use in the general population is described in the
National Epidemiologic Survey on Alcohol and Related Conditions (NESARC):
Whites, Native Americans, and Hispanics have a higher prevalence of
dependence than do Asians, but no published data about physician addiction
have been reported using ethnicity as an independent variable.
In summary, though the prevalence of addiction to all substances appears to
be about the same as in the general population, currently, physicians are less
likely to consume tobacco and more likely to use opioids and sedatives.
Research data suggest that physicians consume more alcohol than the general
population.
CHARACTERISTICS OF PHYSICIANS
WITH ADDICTION
Age and Gender
In a 2008 analysis of more than 1400 medical students, residents, and physicians
at the same southeastern treatment program, Earley and Weaver (unpublished)
noted an age range from 25.3 to 83.7 years, with a median age of 45.8, the ages
distributed in a bell curve (Fig. 49-1). This was a convenience sample of
physician–patients who had been mandated to treatment and is not representative
of all physicians.
Figure 49-1 Distribution of physician age at presentation to

treatment.
Males account for the majority of treated physician addiction cases, with
reported ratios approximately 7 to 1 (33). This contrasts with the 3-to-1 male-to-
female ratio in the physician population at large (34). Although fewer females
than males have drinking problems, female physicians are more likely to report
unhealthy alcohol use by the end of medical school (3). A study from the United
Kingdom reported that incoming female students were nearly twice as likely as
the age-matched general public to be drinking at a moderate or greater risk level,
while males drank at levels similar to nonmedical student controls (35).
At intake into one of four PHP programs, female physicians were more
likely to be younger and to have medical and psychiatric comorbidity (36).
Female physicians were more likely to have past or current suicidal ideation and
were more likely to have attempted suicide regardless of whether they were
under the influence or not. Wunsch et al. report that female physicians are more
likely to use sedative–hypnotics than are men (36).
Specialty
Bissell and Jones (37), writing in 1976 about 98 physicians, were among the first
to systematically parse this cohort by specialty. Using a follow-up questionnaire
of physicians in Alcoholics Anonymous, she noted that psychiatrists and
emergency medicine physicians were overrepresented in Alcoholics Anonymous
(overrepresentation defined as a percentage of a cohort that is higher than
predicted by the percentage of that cohort in the population of physicians at
large). Hughes et al. (18) surveyed 5426 physicians regarding substance use;
they found the self-report of pre–DSM5-defined substance abuse or dependence
was highest in psychiatrists and emergency medicine physicians and lowest in
surgeons and pediatricians. This questionnaire did not break down the substance
used or its legality.
A synopsis of the literature on addiction rates by specialty appears in Table
49-1, which covers multiple authors and modes of analysis. The combined
literature looks at the breakdown by specialty from multiple angles (treatment
presentation, self-report, and medical board and PHP data); the data consistently
purport that psychiatry and emergency medicine physicians have higher rates of
unhealthy substance use. Table 49-1 also suggests that family practice physicians
might be overrepresented, and pediatricians and pathologists appear to have a
lower prevalence of addiction.
TABLE 49-1 Review of Research on Addiction Rates by

Specialty
PHP/MB, physician health program or medical board record study.
The problem of addiction in anesthesiologists continues to attract research and

debate. Lutsky et al. (17) noted that anesthesiologists were more likely to use
cannabis and psychedelics when compared with medicine and surgery physicians
but suggested caution in the interpretation of these data owing to age differences
between the medicine and surgery cohort and the anesthesiology cohort. Talbott
et al. (38) note that anesthesiologists account for 5% of all physicians, yet they
account for 13% of all physician–patients in a residential treatment program.
Self-report studies by Hughes et al. noted a low overall rate of substance use in
anesthesiology, both in residency (19) and after completing training (18). Prior to
the widespread use of fentanyl in general medicine, Lutsky et al. (17) found that
the use of fentanyl (and its congeners) occurred only in anesthesiologists.
Merlo et al. (43) and McAuliffe et al. (44) have recently hypothesized that
anesthesiologists may be sensitized to opioids and propofol through the
inhalation of picograms of these potent agents in the operating room air. Assays
of operating room air detected these agents, especially when taken near the
expiration point of the anesthetized patient. This hypothesis rests on an uncertain
foundation (the assumption that the quantities of these agents are sufficient to
produce sensitization and that the resultant sensitization directly contributes to
the etiology of addiction) but does introduce additional avenues of research.
Anesthesiologists appear to use highly potent opioids more frequently and
are strikingly overrepresented in treatment settings. Access to large quantities of
these high-potency opioids (and other drugs) in the day-to-day practice of
anesthesia is the most likely culprit for the prevalence of anesthesia personnel in
treatment settings. Please refer to the section below on anesthesiologist reentry
for additional information.
DRUGS USED
Alcohol
Two types of studies are used to assess the types of drugs used by physicians:
anonymous questionnaires (7,16–18,20) and self-reports of drugs of choice of
physicians as they appear in treatment or monitoring programs (38). Both types
of research underscore that alcohol is, as expected, the most frequent primary
substance used by physicians, just as it is in the general population.
Tobacco
Tobacco use disorder has been suggested as a risk factor for alcohol and other
drug use disorder in physicians (45) as in the general population (46). Tobacco
use in physicians has decreased over time; Vaillant et al. (22) reported that 39%
of physicians acknowledged smoking 10 or more cigarettes per day in 1953; this
decreased to 25% in 1968 (47). Nelson et al. reported that smoking among
physicians declined from 18.8% in 1976 to 3.3% in 1991 (48). In an earlier era,
physicians took part in magazine advertising extolling the “soothing” and
“cooling” properties of menthol cigarettes on the airway. In a 1996 study,
Mangus reported 2% of medical school graduates were current smokers (23).
From the earlier data, emergency medicine and surgery physicians are twice as
likely to smoke as are other physicians (18). Preliminary data from Stuyt et al.
(49) strongly correlate the continued use of tobacco with subsequent relapse into
other drug or alcohol use, underscoring the association of tobacco use with
addiction in physicians.
Opioids
Opioids are the second most frequently used substance by physicians presenting
for treatment (50). This finding has been remarkably stable over time, but the
type of opioids used continues to change. Hughes et al. (18) differentiate opioid
use into the major opioids (morphine, meperidine, fentanyl, and other injectable
narcotics) and the minor opioids (hydrocodone, lower-dose forms of oxycodone,
codeine, and other oral drugs). Discriminating in this manner, they reported that
family practice and obstetrics and gynecology specialists have a higher
probability of using minor opioids. When compared with all physicians, the
study reports that anesthesiologists were less likely to use minor opioids, with a
trend toward an increased use of major opioids. If one assumes that use of major
opioids results in a more aggressive manifestation and progression of addiction,
this would partly account for the overrepresentation of anesthesiologists over
other specialties in physician treatment programs (38). Several authors
(18,20,51) posit that exposure to drugs in the workplace leads to higher use of
those workplace drugs. In a similar manner, family medicine and obstetrics and
gynecology physicians are frequent prescribers and use more minor opioids than
other specialties (18).
Cocaine
Older literature noted that specialties that employed cocaine in the course of
their work (ophthalmology, head and neck surgery, plastic surgery, and
otolaryngology) showed a trend (not statistically significant) to higher cocaine
use (18). Cocaine use among physicians has shifted to illicit sources more
recently, presumably due to decreased medical use and increased hospital
pharmacy controls. Cocaine use is more common in emergency medicine
physicians, presumably from street sources. Several authors (51,52) have
speculated that the personality style of these specialties attracts them to these
drugs, although most studies on the question of an “addictive personality” have
not supported this theory.
Amphetamine
Physicians use amphetamines from two sources, as in the general population. A
subset of physicians who are prescribed amphetamine and other stimulants for
attentional disorders go on to develop a substance use disorder as in the general
population (53). The pressures of premedical and medical school education and
prolonged hours on duty during residency may promote trial use of stimulants.
Methamphetamine use is 5 to 10 times higher (54) in urban men who have sex
with men. This is mirrored among physicians; most PHPs report that the vast
majority of physicians who use methamphetamine are men who have sex with
men.
Benzodiazepines
One hypothesis of substance use among physicians suggests that the physicians
themselves might more commonly use drugs that are used and helpful in a
physician’s line of work. Survey-based studies report that psychiatrists have a
greater misuse of benzodiazepines; 26.3% report using unsupervised
benzodiazepines in the past year, in comparison with 11.4% in other physician
groups (18). Although unsupervised use does not impute a substance use
disorder, the high rate of benzodiazepine use is reflected in the
overrepresentation of psychiatrists in treatment.
Propofol
Eighteen percent of anesthesia training programs report cases of propofol use
among trainees (55) and its prevalence has increased fivefold in the past decade
(55). Wischmeyer et al. identified 25 anesthesia personnel with propofol use; 7
died as a direct result. This study described a positive correlation between
hospitals with easy availability and subsequent propofol use. High availability
was defined as little or no control over drug access within the training hospital.
Although propofol use often shows up in training, use can occur later in medical
practice. In contrast, propofol use in nonmedical personnel is extremely rare;
only one such case has been reported in medical literature (56).
Propofol use has recently gained the national attention after the death of pop
star Michael Jackson in 2009. Increasing reports of propofol use (57) and
research about its addicting qualities have resulted in the Drug Enforcement
Administration (DEA) placing fospropofol (58) under Schedule IV and a
proposed Schedule IV for propofol as well (59).
Even among healthcare professionals, propofol dependence represents a
small portion of the treatment population at 1.6% or 22 of 1375 treated
physicians (60). Its incidence appears to be increasing over one 20-year study
(60). Other characteristics of this cohort of 22 propofol-dependent physicians
noted a tendency toward the female gender, higher incidence of early-life
trauma, concomitant mood disorder, and physical trauma resulting from
substance use (60).
Cannabis
Cannabis is the second most common drug used among medical residents (21),
second only to alcohol. A 2000 UK study reported 14% of male and 23% of
female incoming medical students reported current use of cannabis (35).
Physicians from all specialties use cannabis, with emergency medicine,
orthopedics, plastic surgery, anesthesiology, and psychiatry physicians
displaying elevated odds of cannabis use over physicians as a whole (18,61).
When added to the trend toward legalization of cannabis in many states, a
conundrum emerges: Should those in oversight positions send physicians who
test positive for cannabis for clinical evaluations (62)? What if the physician has
a “medical marijuana” prescription or card? Following the November 2016
elections, 63 million Americans now live in states that have legalized cannabis—
even as federal regulations continue to (a) criminalize possession and (b) deny
medical utility for cannabis used as medicine (so-called “medical marijuana”
products).
Other Drugs
Physicians are also found to use drugs that are not generally available or not
recognized as having an addictive potential by the general public. Skipper (63)
reported that tramadol was the third most frequent opioid mentioned by
physicians “although it was rarely the primary drug of choice” in a study of 595
physicians from two state PHPs over an 8-year period. Moore and Bostwick (64)
described two cases of ketamine use in anesthesiologists; some professional
treatment programs see several physicians with addiction to ketamine per year.
RISK FACTORS
The risk for addiction in physicians is an area rich in speculation and poor in
research.
Genetics
The strongest predictor of alcohol or drug problems in physicians is the same as
in the general population: a family history of alcoholism or pre–DSM5-defined
drug dependence (3). Of importance in this regard is the work of Moore (45)
who observed several genetic and substance use factors in medical students that
later correlated with unhealthy alcohol use including non-Jewish ancestry
(relative odds [RO] = 3.1), cigarette use of one pack or more per day (RO = 2.6),
and regular use of alcohol (RO = 3.6).
Personality
All physician specialties are burdened with common stereotypes, and it has long
been tempting to speculate about causal personality factors in the development
of addiction disorders among physicians, although decades of addiction research
have never found evidence to support an “addictive personality.” Observed
physician personality dynamics may be a consequence or an epiphenomenon to
the true etiology of the addictive process. With the preceding caveats, it is still
interesting to review published speculations about physician personality types
and addiction. Although personality issues may or may not be causative in
addiction, they often play an important role in the progression, presentation, and
treatment of addiction disorders and therefore are covered below.
McAuliffe et al. (7) noted “sensation seeking” as a personality factor that is
correlated with drug use among physicians in training. These authors speculate
that such individuals gravitate to specialties such as emergency medicine.
Emergency medicine physicians may self-select high-risk or illicit drugs owing
to the same personality characteristics that draw them to their specialty. Hughes
et al. (18) reported emergency medicine physicians were twice as likely to use
cannabis as other specialties. Their data also suggested cocaine use was higher in
this cohort. However, this hypothesis is not supported by data from other
specialties also thought to attract sensation-seeking individuals, such as surgery,
which is not overrepresented in treatment settings.
Bissell and Jones (37) suggest perfectionist behavior and a high-class
ranking are risk factors for addiction. This is supported by the work of Roche et
al. (65), who noted that anesthesiologists with addiction are often in the top 10%
to 20% of their class. Udel (66) notes that obsessive compulsive personality
disorder (or traits) is the most common personality diagnosis of physicians
presenting for treatment. No data differentiating the occurrence of compulsive
traits in physicians with or without addiction are available. However, compulsive
traits are beneficial in all physician training and work. Zeldow and Daugherty
(51) and Yufit et al. (52) speculate that the introverted and introspective qualities
as well as a drive for an internal locus of control are partially responsible for the
drug of choice in this population.
Drug Access
O’Connor and Spickard (1) described a subset of physicians who began using
benzodiazepines and opioids only after receiving prescribing privileges. Drug
access may also account for changing addictive drugs within the opioid class
over time. Green et al. (67) in 1976 and Talbott et al. (38) in 1987 reported that
the predominant opioid used by physicians at the time was meperidine. A more
recent (2005) review of the Michigan and Alabama Physician Health Program
reports hydrocodone as the number one opioid used (40% of all opioid cases),
meperidine dropping to 10% of cases (63). The most likely hypothesis for shifts
in the drug of choice by physicians over time is the changing prescribing
patterns and availability of these drugs in the marketplace.
Biologic Effect of the Drug of Choice

The neurobiologic effects of drugs used by those with an addiction color the
characteristics of the addiction disorder itself. Drug-of-choice characteristics also
skew the characteristics of the physician–patients arriving in treatment programs.
For example, all opioids produce intense tolerance, resulting in histories of ever-
increasing doses. Drug hunger drives the progressively tolerant physician to
divert increasing quantities of opioids from work and, in doing so, increases the
probability of detection. This partially explains why treatment-seeking or
treatment-mandated physicians tend to present disproportionately with histories
of opioid use.
High-potency opioids (such as fentanyl) when consumed parenterally
produce a rapid downhill course owing to the development of remarkable levels
of tolerance. The accelerated course of addiction from the most potent opioids
can be postulated as contributing to deaths and the high percentage of
anesthesiologists seen in physician treatment programs. Collins (4) has
suggested that rapid onset (and the resolution of tolerance with brief periods of
abstinence) and/or low therapeutic ratio may account for the high mortality rate
in propofol-, fentanyl-, sufentanil-, alfentanil-, and remifentanil-using
anesthesiologists. Increased awareness along with checks and balances to
account for the remaindered volumes of fentanyl used in hospitals may detect
diversion more rapidly and save lives of anesthesia personnel (68–70).
ADDICTION COMORBIDITY
Thought and Mood Disorders
Physicians suffer from a spectrum of emotional and psychiatric problems similar
to the general population. Although it is unclear whether physicians have higher
or lower rates of unipolar depression, physicians who successfully complete
suicide are more likely to have a drug use problem in their lives, self-prescribed
psychoactive substances, a recent alcohol-related problem, a history of
emotional problems prior to 18 years of age, and/or a family history of unhealthy
alcohol use and/or mental illness (71). Substance dependence, self-criticism, and
dependent personality characteristics are associated with depression in
physicians (72). Bipolar disorder (types I and II) may contribute to the intensity
of addictive disease in physicians, particularly for drinking during manic
intervals (73). Bipolar disorder is more often seen, probably because it is more
compatible with work—as long as the mania is constrained to the hypomanic
range. However, physicians with addiction rarely have comorbid primary
schizophrenia and related thought disorders.
Pain
PHPs are working with an increasing number of physicians with chronic pain
and analgesic opioid use, many of whom have become physiologically
dependent. In turn, an unknown percentage of those go on to develop the disease
of addiction. Eventual addiction is thought to be more common in patients with
pain disorders (74), and, when combined with the 25% of physicians who self-
prescribe (16), a perfect storm of high-risk factors emerges. Physicians who have
significant pain and addiction disorders pose diagnostic, treatment, and
management difficulties for assessors, treatment providers, and the PHPs.
Regulatory issues cloud the treatment of addicted physicians with pain: Should a
formerly addicted physician on opioid medications be allowed to practice? Is it
logical for state boards to prohibit ongoing methadone or buprenorphine
treatment but permit potent opioids for pain management? These complex
questions often result in ideological or political conclusions rather than
evidence-based answers. Scientific data on the safety of physicians practicing
while taking opioids, whether addicted or not, are sorely lacking. Insufficient
data are available for a definitive decision, but appropriate concern remains
(75,76).
Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) and alcohol use disorder are closely
intertwined (77), and PTSD increases the probability of addiction relapse in
stressful contexts (78). However, no studies about the prevalence of PTSD in
physicians have been published. Physicians, like anyone else, are not immune
from prior trauma histories. Several physician specialties, including emergency
medicine physicians, trauma surgeons, and military psychiatrists, can be
traumatized by events at work. Although combat exposure is known to increase
the statistical risks of addiction in veterans, no data exist to indicate whether
such trauma increases the likelihood of substance use disorders in military
physicians. And, treating trauma can be, in itself, traumatizing to the caregiver.
THEORIES OF ADDICTION AMONG

PHYSICIANS
The natural history of addiction is, on the surface, similar in physicians to that of
any other person with drug or alcohol use disorder. McAuliffe et al. (79) report
that 27% of medical students and 22% of physicians had family histories of
alcohol dependence. Lutsky et al. (17) and Domino et al. (80) put this figure at
almost 75%. Moreover, the genetic research literature now supports inherited
genetic vulnerabilities for all major classes of addictive drugs.
Clark et al. (27) reported that excessive alcohol consumption in medical
students was positively associated with better grades in the first year and a
strong tendency toward better scores on Part I of the National Board of Medical
Examiners test. Unhealthy alcohol use was found to have no discernible impact
on clinical rotations in years 3 and 4 of medical school in this study. This led
Clark to speculate that hard-drinking students may be prone to discount
warnings and feel invulnerable to the effects of alcohol; their own internal
experience does not match cautionary information provided to them during their
medical education. This may exacerbate an emerging “us” (doctors) and “them”
(patients) view of the world. These findings mirror extensive research by
Schuckit, who consistently demonstrated that less intense, early-life, and
adolescent reactivity to alcohol increases the risk for the later development of
alcoholism (81,82).
Stress and burnout are often cited by the physician–patient as the primary
agent that drives self-medication. Burnout is on the rise (83), but its exact
correlation with substance use and addiction is unclear. However, when
combined with difficulties asking for help (11), it leads to self-prescription, a
slippery slope at best (84). Physicians in treatment for substance use disorders
report that the stress of medical training, when combined with social isolation,
provides a fertile soil for the growth of drug consumption (4). Jex et al. (85)
suggest that the physician’s unhealthy response to stress is a more important
determinant of addiction than the ubiquitous presence of stress itself.
No evidence supports a specific professional personality type as being a
determinant in addiction (86,87); however, personality dynamics specific to
physicians naturally must play a role during the illness and its treatment (88,89).
Vaillant et al. (90) have suggested that physicians commonly experience an
emotionally barren childhood. Johnson and Connelly (91), who identified 72%
of a 50-physician sample hospitalized for addiction as experiencing parental
deprivation in their childhood, echo this postulate. Khantzian (92) eloquently
depicts the physician’s efforts at caring for others as a partially successful
sublimation; caregiving of others becomes a partial repair of deficits in parental
nurturance. Tillett (89) described this dynamic in helping professionals as a drive
to “compulsively give to others what he (she) would like to have for himself
(herself).” When this transformation fails, the addiction-prone physician, lacking
other methods of self-care, has a propensity to turn to substance use.
Physicians in the act of saving human lives develop a varying degree of
omnipotence (13). This omnipotence, when combined with knowledge of the
drugs they prescribe, may produce feelings of invulnerability regarding drug or
alcohol use. Vaillant (25) has speculated that self-prescribing (related to
physician self-sufficiency and false omnipotence) plays a permissive role in the
development of addiction in physicians. Physicians’ illusion of mastery over
pharmaceuticals keeps them from distinguishing their lack of control over
substance use, opening the door to experimentation and, if continued, a
progressive deterioration in their drug use.
Genetic vulnerability and the priming effects of the drug itself remain the
most evidence-based etiologies of addiction. Childhood experiences, medical
school training about pharmaceuticals, and the life-and-death nature of a
physician’s work certainly modify the quality and progression of a nascent
addiction problem. Physicians are taught in medical school and residency (and
often in their childhood) to appear self-sufficient and in control. This façade of
competence establishes the framework for a secretive and duplicitous
personality, and once the physician is using substances, his or her secret garden
provides a fertile soil for additional substance use. Concealment and lying are
not qualities that support a mature approach to marriage, life, and work. The
illicit and secretive qualities of addiction promulgate additional personality
regression.
The physician’s behavior deteriorates first at home, then with friends, and
finally surfaces at the workplace. By the time a physician exhibits problems at
work, significant familial discord (marital strife, divorce, difficulties with acting
out in children) commonly exists. Rarely does the family “turn in” a spouse or
other family member with presumptive addiction (93). Often, a colleague or
other hospital staff is the first to voice concern. The physician is then confronted
at work when an undeniable incident occurs or a series of smaller incidents push
colleagues and the hospital medical staff to confront the doctor. An active PHP,
especially one that is supportive and confidential, can be very beneficial in
reducing the threshold for reporting to punitive agencies and, thus, can promote
early detection. Most physicians arrive in treatment with thin scraps of their
façade remaining. They exhibit a demeanor of superiority and knowledge, deny
any loss of control, and have a need to appear competent, in stark contrast to
their crumbling lives.
IDENTIFICATION, INTERVENTION,
AND ASSESSMENT
Identification
Physicians present with a broad spectrum of symptom severity, from a physician
self-identifying a drinking problem while in couples’ therapy all the way to a
physician who is found apneic and asystolic on the floor of the operating room
bathroom. In the past, denial, shame, and fear of reprisal tended to keep the
physician from seeking proper help until significant external consequences
coalesced (2). In more recent years, the emergence of clinically oriented,
supportive, and confidential PHPs has stimulated earlier reporting, by either self-
or colleague referral. Physician–patients with substance problems have often had
years of familial and social discord while struggling to maintain acceptable work
performance, until this last refuge, too, collapses. Thus, disturbances of social or
familial functioning may be more sensitive indicators of early substance use
disorder in the physician. Unfortunately, the family often protects the physician
with a substance use disorder who serves as the “breadwinner.”
A variety of work-related behaviors can be clues to substance use. O’Connor
and Spickard (1) describe conditions and warning signs that can help detect
addiction (Table 49-2). Talbott and Wright (93) and Talbott and Benson (94)
have independently reported a similar list of behavioral signs of addiction in the
physician.
TABLE 49-2 Warning Signs of Unhealthy Substance

Use in Physicians
Adapted from O’Connor PG, Spickard A. Physician impairment by substance abuse. Med Clin North Am.
1997;81(4):1037-1052.
If problems are not addressed early, the doctor’s work quality and attendance
often suffer. In contrast, if a physician obtains drugs at work (eg, samples from a
drug closet or drugs diverted from the OR or ICU), he or she displays the
opposite behavior—volunteering for additional shifts, arriving early for work,
and signing up for more complex (ie, easier drug access) cases.
Modes of Intervention
Several comprehensive guides to physician intervention have been published
(2,5,10,95,96). In recent years, PHPs have become very skilled at directing the
physician–patient into treatment without overly aggressive confrontation and
ultimatums. PHPs commonly conduct a comprehensive evaluation or send a
physician for evaluation by a third party. The physician in question is told about
existing concerns (often without divulging the source of information) and the
importance of resolving said concerns. Ultimately, the goal of intervention is
early detection of whatever problem is causing concerns.
Most physicians appreciate their duty to public safety. Once a well-being
committee at a hospital or the PHP points out the need to determine if a health
problem is present, this sense of duty, combined with some level of self-concern,
can motivate a physician to obtain a proper evaluation. A minority of physicians,
especially those who have in the past felt assaulted by a legal process or have
undergone previous interventions, require additional orchestration with partners
or employers who then help the physician get to the evaluation and/or treatment
process. Regardless of the path to the door, physicians commonly arrive with a
thinly fabricated story depicting their entry into evaluation or treatment as self-
motivated.
Most states have reporting laws that require hospitals and colleagues to
report a physician to the state PHP or their state medical board who is suspected
of being impaired by alcohol or drugs. Treating physicians must have knowledge
of the laws in their state before beginning treatment of physicians with addiction
issues. In 2001, The Joint Commission pressured hospital organizations to
address the wellness of their medical staff through standard MS2.6 (97). The
Joint Commission standard has helped formalize a physician health process in
most hospitals and formalize the support and intervention network in hospitals.
Many PHPs are able to assist the hospitals in meeting this standard. Hospital
wellness committees can be effective in early identification and referral of
physicians if the process maintains a balance of compassion with a firm directive
hand.
In contrast, the primary agenda of hospital credentialing and executive
committees is maintaining quality of care and risk management strategy. When
concerns are raised, including concerns about potential impairment, they utilize
letters of concern, sanctions, and decredentialing to protect the hospital and the
public. Wellness committees, on the other hand, focus on the health of providers
within the organization. If a wellness committee attempts to get a provider help,
such help would be scuttled (and appear quite disingenuous) should it become
known to the organization credentialing body with the potential for resultant
action. Therefore, a firewall should be maintained between the wellness and
credentialing/executive committees.
If a substance use disorder is not caught in its early stages, the possibility of
impairment arises. Thus, the primary public health goal of PHPs is to diagnose
and treat physicians early in the course of their illness. Impaired supervisory
physicians are no longer protected and enabled by their juniors. In a study of
impairment of all types (not focused solely on substance-induced impairment),
Igartua (98) reported that 7% of residents in her survey reported working with an
impaired physician supervisor. Reuben and Noble (99) reported that 72% of
house officers would report an impaired attending physician.
Assessment
Responses to an evaluation request vary widely. Some physicians are quickly
identified and agree to cooperate with their treatment needs or at least with an
outpatient evaluation. Physicians who are more entrenched in their addiction,
who have more complex presentations, or who are frankly resistant need formal
and more extensive assessment and a methodical, nonshaming confrontation of
their denial complex. In all cases, use of the ASAM Criteria can be helpful
toward determination of level of care decisions. Timely and proper diagnosis is
best made by an interdisciplinary evaluation using the guidelines established by
the Federation of State PHPs (100). Assessment can be completed at the least
intensive level of care that results in a comprehensive view of the patient and his
or her family and social system. The examination process must prevent the
assessed physician from hiding continued drug use and withdrawal as well as
addiction-related interpersonal behaviors. Because of the complexity and
comprehensive nature of these evaluations, in some—but not all—cases, it may
be helpful to conduct them in a higher level of care (such as a residential or
partial hospitalization setting) where the evaluation staff are in continuous
conversation about a case, able to adjust the process rapidly and obtain the
broadest understanding of the individual. When the physician is removed from
his or her work role, the evaluation team is able to observe the physician when
they are outside of the provider role; this affords a broader understanding of the
individual when the protective physician cloak is removed (101). Allowing
physicians to self-select an evaluator commonly results in their choosing a friend
or colleague or someone who lacks the necessary expertise in the nuances of a
physician addiction evaluation. This results in an inadequate or limited
evaluation and thus a missed chance at early diagnosis. Therefore, most PHPs
have established criteria and maintain a list of competent evaluators. PHPs often
direct physicians to an outpatient, an intensive outpatient, or a residential
evaluation based upon the complexity of the case at hand.
The evaluation should include information from, but should not be carried
out by, a current or past therapist, psychiatrist, or other caregiver. Many PHPs
direct the evaluation to a multidisciplinary team composed of an addiction
medicine physician and/or an addiction psychiatrist and include psychological
and neuropsychological testing, family assessment, review of previous medical
records, and the collection of collateral information from coworkers, hospital
employees, friends, and PHPs themselves. A broad array of information from all
available resources is critical to an accurate assessment. Table 49-3 outlines the
purpose of each component of a comprehensive physician addiction evaluation.
TABLE 49-3 Components of a Suggested
Comprehensive Physician Addiction Assessment
a
All components of the evaluation contribute to determination of whether an addiction disorder exists, the
level of care needed, and treatment planning for ongoing care, if indicated.
The team involved in a multidisciplinary evaluation meets repeatedly during the

evaluation and, once again when all data have been collected. Final diagnoses
and recommendations are best produced by discussion among members of the
evaluation team. The patient then meets with one or all members of the
evaluation team to review the diagnosis and recommendations. The patient may
elect to involve a family member. The evaluation team is best served by
including the PHP or other referral source in the summation session; this action
decreases confusion and splitting regarding the outcome. A comprehensive,
integrated report is commonly sent to both the physician–patient and other
relevant parties (with appropriate Release of Information authorizations).
TREATMENT
Approximately a dozen programs in the United States have experience and
specialized expertise in the treatment of physicians and other health
professionals with substance use disorders; some programs have more than 30
years of experience and have treated thousands of addicted physicians. However,
some states are trending toward increased law enforcement actions against
addicted physicians, as opposed to treatment. California, for example, decided to
“sunset” the Physician Diversion Program in 2009, and it is far from clear what
kind of structures will replace it. Strong political voices are recently heard to say
that addicted physicians deserve no “strikes” and that they are, in essence,
disposable in a competitive medical economy.
Clinical Considerations in Treating Addicted

Physician–Patients
It has been alleged that physicians “make the worst patients” (102). Physicians
often deny symptoms of any disease, seek substandard care, and put off
appropriate care for serious symptoms (103). As in any other medical situation,
the physician–patient who enters addiction treatment has difficulty giving up the
provider role and assuming the obligations of a patient (101,104). In treatment
settings with an admixture of physician–patients and nonphysician–patients, the
treatment program must set firm limits, prohibiting the physician from providing
medical advice or care to other patients. If a patient is the only physician in a
given treatment setting, that patient will likely remain or lapse into his or her
physician’s role the first moment another patient asks for medical advice or for
stories from his or her career. This shifts focus off of the physician–patient
decreasing the efficacy of his or her treatment. By contrast, when a physician
falls into self-diagnosis, it is best to use this as grist for the therapeutic mill.
Physicians will also attempt to fit the treatment into what they know:
schooling and testing. Thus, they have little trouble learning the didactic parts of
treatment. Physicians early in treatment may arrive at a group therapy session
with pen and paper in hand, hoping to glean one piece of information that will
rocket them into recovery or, at the very least, accelerate their discharge. At the
very least, they can parrot the prevailing recovery orthodoxies to the staff. The
transformation required of all patients in addiction treatment is an emotional,
interpersonal, and, for many, a spiritual shift. Physicians have little experience in
this area. They often become stuck trying to obtain an “A” in treatment and, in
this way, miss the necessary wholesale changes that are needed to recover in
earnest. When staff attempt to correct the physician’s approach to treatment, they
risk becoming ensnared in the physician’s tendency toward excess perfectionism.
The resultant hostile projection produces negative transference and a thinly
veiled contempt for “less educated” therapists and staff (104).
Physicians work and interact in an environment filled with physical and
emotional pain. To succeed, they must at times distance themselves from the
strife around them. When combined with an achievement-oriented childhood,
the physician–patient defaults to intellectualization of his emotional experience
or, on occasion, frank alexithymia (without words for feelings) (105,106).
Treatment will necessarily reacquaint the physician with the subtle nuances of
feeling states, often confused or conflated with craving or “stress.”
One particularly difficult emotional state is shame. Most addiction patients
view their substance use and their lives through a lens of shame—and physicians
seem to have a surfeit of shame. Fayne and Silvan (104) note that a key task in
recovery is an honest appraisal of how the physician’s addiction has interfered
with his ability to function as a physician. This requires a vigilant therapeutic
group that models self-disclosure and self-examination. The physician, owing to
childhood and training-induced drives for accomplishment and perfection, risks
turning the task of self-examination into self-loathing. Treatment of such
individuals mandates that the treatment staff and community encourage fearless
self-examination without inadvertently pulling the hair trigger of the physician’s
self-loathing. When in the state of shame, an additional defense of the
physician–patient is to psychologically freeze. The precarious management of
shame is further complicated by the patient’s transference and the therapist’s
countertransference that arises when a bright physician–patient seems incapable
(or willfully resistant) to the self-examination necessary for recovery.
Working with addicted physicians requires understanding of the dynamics of
addiction and the distinct but highly interactive elements between addiction and
the personality. Inexperienced or overly biased treatment providers tend to label
the psychological effects of addiction as personality issues, or, conversely, they
view long-standing personality dynamics in the physician–patient as addictive
thoughts and actions. A balanced understanding and therapeutic approach require
a healthy respect for both schools of thought. Addiction uses the specific
personality dynamics of the physician–patient to serve its own ends,
exaggerating and driving maladaptive forces to ensure its own survival.
Conversely, the addictive process generates complicated internal and
interpersonal pathology.
It is tempting to establish a cause-and-effect relationship between
nonaddiction psychiatric disorders and the disease of addiction itself. Such a
path often colludes with the patient’s denial system. A more powerful viewpoint
is to envision a patient’s addiction and other mood and personality issues as
distinct disorders that are independent but deeply collaborative and mutually
reinforcing.
Social and legal issues only further confound the type and course of
treatment. Because of all the aforementioned issues, treatment is by its nature
different in physicians. Medical boards, the general public, PHPs, and the
physician him- or herself have low tolerance for the potential public harm that
can occur when a physician becomes addicted; they are exquisitely intolerant of
multiple relapses. This flies in the face of the nature of addiction: a disease
characterized by remission and relapse. The societal pressure to “have a perfect
recovery” creates a maladaptive alliance with the physician–patient’s own
perfectionism (107).
Characteristics of the Treatment Setting

The treatment of physicians involves a prolonged continuum of care. When a
physician leaves his or her initial treatment setting and returns to work, this is
described by the unfortunate and inaccurate vernacular of having “completed
treatment.” In fact, what physicians are asked to do in the second phase of
treatment is in many ways more comprehensive care than what many patients
receive during their primary treatment (108). This “posttreatment” monitoring
commonly involves weekly group therapy sessions, peer support groups,
aftercare groups, individual and family therapy, self-help group attendance, drug
testing, and worksite monitor reports for 5 years or more.
The confluence of known difficulties engaging physicians in treatment, the
public demand for safety, and liability issues involved in allowing a physician to
work while in outpatient addiction treatment have promoted physician-specific,
long-term residential addiction treatment programs (101). A paucity of literature
exists about the efficacy of less intensive treatment, but fair results have been
reported by Dilts et al. (109) and Reading (110). Smith and Smith (111) reported
a small cohort of physicians treated in low- and high-intensity care, with
substantively better results when longer-term residential care was employed.
DuPont et al. (30), reviewing 16 state PHPs over 5 years, noted that 78% of
physicians who required treatment went to residential treatment for 30 to 90
days, followed by less intensive outpatient treatment. The remaining 22% of
treated physicians went directly to outpatient treatment. Hospitals, malpractice
carriers, regulatory boards, health insurance companies, and family and friends
have expectations of continuous abstinence. Most medical boards and,
increasingly, malpractice insurance companies (who in many states have become
a more powerful threat) penalize a physician if he or she relapses, even a single
time. Owing to the research (albeit limited) on the effectiveness of residential
treatment and the penalty placed upon relapsing physicians, most physician–
patients are encouraged to attend longer treatment programs than are
nonphysician peers (112).
Skipper (112) outlined the treatment of the impaired health professional. He
reported that all physician-specialized treatment programs use a 12-step
philosophy as the core component of treatment. Such programs have proven
effectiveness with physicians (30,108,113,114). Studies show that if abstinence
is the desired outcome point, consistent involvement with 12-step meetings
produces the best results (115–117). All physician treatment programs reviewed
by DuPont et al. (30) utilize family therapy, and most offer a brief
psychoeducational family program sometime in the physician’s treatment (1).
Family participation also leads to a better outcome (118). Family members move
through their own difficulties accepting the addiction diagnosis, anger at the
physician–patient, and fear of loss of prestige and financial security. The initial
goal of family treatment is to redirect the hostility away from the patient (as well
as the treatment providers and PHP) toward the addictive illness itself, using this
energy to build healthy and constructive family dynamics, focused on relapse
prevention.
Physician-specific groups allow self-disclosure and sharing of alcohol- and
drug-related behaviors that risked or, in rare cases, caused patient harm. Such
violations of the Hippocratic Oath generate shame. Once articulated, such lapses
in physician responsibility are best linked to the addictive disease and away from
the core self. Disclosures of the deepest violations of core values in profession-
specific groups can, if properly managed, provide relief and help the physician
differentiate his or her actions while addicted from their self-concept. Physician-
specific groups serve a different, more pragmatic, but equally important,
purpose. Most physicians have work-related triggers (eg, drug access at work,
prescription pads, and locations in the office or hospital where use occurred). In
these groups, participants explore work triggers and develop medically specific
relapse prevention plans. On this practical level, physician-specific groups also
address the myriad of other issues physicians face when returning to practice,
such as the difficulties of seeing their patients in AA, how to respond to
questions from peers and other staff about their illness, Drug Enforcement
Administration prescribing restrictions, and continued management of drugs and
prescriptions in the office or hospital. These needs require healthcare
practitioner–specific therapy, preferably in a group setting to increase
acceptance, decrease the unique aspects of shame, and teach skills of healthy
interdependence (101).
Addiction medicine utilizes several pharmacologic agents in the treatment of
addiction. Most programs that treat physicians with alcohol use disorder utilize
one or more medications including disulfiram, oral or injectable naltrexone,
acamprosate, and/or topiramate. Medications are also useful in the treatment of
physicians with opioid use disorder. The opioid antagonist naltrexone is
prescribed for physicians who, upon return to practice, have continued easy
access to opioids. It could be argued that monthly injectable naltrexone is
especially desirable because the monitoring program is assured that the
medication is continuously “on board” (88,119). Alternatives such as monitoring
urine for the presence of naltrexone or observed administration of oral doses of
naltrexone may also be used; however, observation quickly lapses replacing
safeguard with false security. Physician treatment programs and PHPs are
currently conflicted about the use of buprenorphine or methadone in physicians
with opioid use disorder. This is covered in the section Controversies.
Ultimately, long-term randomized monitoring of physicians may be the most
essential component of treatment and critical for sustained recovery. Monitoring
and support groups are commonly provided by PHPs or occasionally by the
treatment center itself, as discussed below.
Physician Health Programs

History
The importance of PHPs in supporting and promoting early detection and proper
evaluation and treatment of physicians cannot be overstated. The heart of the
physician’s health movement can be traced back to the founding of the
International Doctors in Alcoholics Anonymous (IDAA) by Clarence Pearson, in
1949 (120). IDAA has grown from 24 physicians, meeting in Pearson’s garage in
Cape Vincent, New York, to an international organization attracting thousands of
physicians and other doctorate-level individuals in recovery from addiction. On
the regulatory side, the Federation of State Medical Boards called for a model
probation and rehabilitation process for addicted physicians in 1958. However,
no meaningful change occurred until 1973 with the publication of the watershed
JAMA article: “The sick physician. Impairment by psychiatric disorders,
including alcoholism and drug dependence” (121). The American Medical
Association (AMA) held its first conference on physician impairment in 1975.
State medical societies organized committees on physician impairment. The
American and Canadian Medical Associations have jointly sponsored
conferences on physician impairment every other year since 1975. Concern from
medical organizations, governing bodies, and hospital regulatory boards resulted
in the state-by-state emergence of PHPs over a period of 25 years. By 2007,
almost every state in the United States has some type of PHP, ranging from one
employee with a $20000 budget to a 1.5 million dollar budget and 19 full-time
employees (9,30). By 2007, PHP programs monitored more than 9000
physicians across the United States (30).
Structure
PHPs have widely different organizational structures and lines of authority. More
than half (54%) of PHPs are nonprofit foundations. Others are part of their
respective state medical association (35%) or the licensing board itself (13%)
(30). All PHPs have written agreements that guide their interaction with their
state licensing boards. Most (59%) of PHPs evaluated in the DuPont et al. study
from 2009 (30) have specific laws that sanction their actions and guide their
operation. PHPs have evolved from two distinct sources. Some PHPs have
descended from committees of a medical board itself and have evolved, with
varying degrees of autonomy from a licensing body. Other PHPs emerged from a
state medical society or other concerned physician groups. The independent
evolution of state PHPs coalesced into a federation in 1990. Many state medical
boards continue to actively monitor some physicians while referring others to the
state PHP. Interestingly enough, one comparison study of a state (Oregon) with
both programs noted that “voluntary diversion program for appropriately
selected physicians may enhance earlier referral and intervention” (122,123).
PHP Activities
Education and Referral
Most PHPs provide education about all types of physician illness (including
substance use disorders) and train local hospitals and physician organizations on
techniques to help identify and report suspected impairment. Even more
importantly, these educational programs offered by PHPs afford the PHP staff
the chance to personally meet and network with medical leadership throughout
their state. This public relations and training effort carried out by PHPs is
important; it helps individuals understand and trust the supportive goal of the
PHP, which in turn promotes early referral. Healthcare organizations have shown
increased interest in these issues, thanks to the recent Joint Commission standard
(currently MS 4.80), which mandates that “the medical staff implements a
process to identify and manage matters of individual health for licensed
independent practitioners. This identification process is separate from actions
taken for disciplinary purposes” (97).
Addiction (both from substance use and gambling) continues to be the most
commonly identified problem addressed by many (but not all) PHPs (30), but
most PHPs address other psychiatric disorders, disruptive and distressed
physicians, and physicians who suffer from other compulsive disorders such as
problematic sexual behaviors. All PHPs offer consultation about substance use
cases, coordinate intake into treatment, and monitor physicians after treatment
through statewide systems. Some PHPs offer initial assessment, triage, and
ongoing therapy groups for the physicians in their state.
PHPs have become more professional, with credibility provided by their
expertise, affiliation with the Federation of State Physician Health Programs, and
other medical organizations, such as the AMA and the Federation of State
Medical Boards. As professionalism has increased, so has their finesse and
ability to carry out educational programs, expanding to a broader range of topics
(stress, burnout, compassion fatigue, sexual misconduct, appropriate prescribing,
etc.). The core concept of PHPs has become clear, to detect problems that lead to
impairment and to intervene and encourage physicians to obtain assistance prior
to damaging their careers or harming patients. Sophistication in dealing with
addicted physicians has increased, in partnership with expert evaluators and
treatment providers. Follow-up monitoring has become much more sophisticated
with additional monitoring tools (hair testing, flexible variations in drug testing,
new tests for alcohol, devices that detect alcohol consumption, and so on). New
software options are facilitating the aggregation and analysis of physician
monitoring records, obtaining reports through online reporting and real-time
oversight. Participant satisfaction with the PHP process, irrespective of whether
they entered voluntarily or through mandate, is quite satisfactory (124).
Abstinence Monitoring
All PHPs track the abstinence status of physicians who enter their program with
substance use disorders; some monitor other addiction disorders. All programs
use random witnessed body fluid analysis (most frequently through urine drug
screens but often including hair, nail, and blood analysis) through an organized
monitoring program. Screens commonly taper in frequency over the course of
monitoring, for a period of 5 or more years (50). Participation in PHP monitoring
is contingent upon the physician “calling in” or checking a confidential website
each day to see whether he or she has been selected for screening. Urine
screening in physician populations requires considerable expertise and accuracy,
since physicians with addiction can use their knowledge to evade detection
(125). Most physician drug panels test for 20 to 25 drugs, including a wide
variety of opioids. Specialty screens for fentanyl, alfentanil, and sufentanil are
necessary in physicians who have used these drugs in the past and/or who have
future access to such compounds. Hair testing can be important in this regard
because fentanyl and its congeners have very brief half-lives but are readily
detected in hair for weeks or months. Physicians also occasionally use more
unusual drugs (ketamine, propofol, tramadol, and dextromethorphan); these
physicians need assessment panels specifically designed to prevent a lapse in
their abstinence to such substances. The screening is also broad as to the drug
types. This breadth prevents switching from one substance to another, as
commonly occurs during the natural course of the addiction disease.
More recently, PHPs began more sensitive testing for alcohol use by
assaying for ethyl glucuronide (EtG) (126,127) and ethyl sulfate (EtS) (128),
liver and lung tissue metabolites of ethyl alcohol. Newer testing for blood
phosphatidylethanol (PEth) has provided a longer detection window for ethanol
consumption. False-positive test results for EtG, EtS, and PEth have been
reported, owing to a combination of environmental exposure and the sensitivity
of the tests (EtG, EtS, PEth) and the low-level production of EtG by urine
bacteria (EtG) (129). The two most common culprits in false positives are
incidental ingestion of ethanol-containing substances (eg, mouthwash) and
topical application of ethanol-based hand sanitizers (especially if inhaled).
Physicians under monitoring are counseled to avoid these compounds. Using an
alternative to ethyl alcohol–based hand sanitizer, such as isopropyl alcohol–
based sanitizers, should be considered.
The length of time a physician should remain in monitoring is unclear. The
best outcome data follow physicians for 5 years or more (50,80,113,114).
Looking at relapses, Domino et al. reported 58% occurred in the first 2 years and
28% in years 3 to 5 and 14% relapsed after year 5. This suggests a cutoff of 5
years or more may be prudent. Using a 60-year prospective study of men with an
alcohol use disorder (not physicians, per se), Vaillant suggested “…analogous to
cancer patients, a follow-up of 5 years rather than of 1 or 2 years would appear
necessary to determine stable recovery” (130). Lastly, a 1995 policy of the
Federation of State Medical Boards stated physicians involved in PHP should be
supervised for a minimum of 5 years; this policy was reiterated in 2011 (131).
Thus, limited data, when combined with a near mandate of regulatory agencies,
have set a time frame of 5 years for PHP monitoring. Additional research would
assist in developing more granularity in monitoring and help determine which
individuals with which conditions and co-occurring disorders need what
intensity of monitoring for what length of time. Some PHPs place selected
participants on career-long monitoring, especially if their substance use has led
to workplace involvement or has caused significant life consequences.
Recovery Support
In addition to urine monitoring, most state PHPs provide some type of group
experiences and behavioral monitoring (eg, attendance records at support groups
and therapy). The most common of these are caduceus groups, a vague moniker
that varies from peer-led groups like 12-step meetings to large therapist-led
groups whose focus varies from discussing a member’s pragmatic concern to
emotional process work in a large group setting. Unlike in Alcoholics
Anonymous meetings, direct feedback and discussion is encouraged in most
caduceus groups. Newcomers may obtain recovery sponsors or guidance from
physicians that are more senior in the network of PHP support groups.
All long-term studies of physicians underscore the importance of 12-step
meetings (primarily AA and NA) as a central part of recovery (50,132,133). In a
study of 100 physicians with an average of 33.4 months after treatment
admission, Galanter et al. (133) noted, “A.A. was apparently perceived by
respondents as the most potent element of their recovery.” Outcome studies in
physicians show impressive abstinence rates, with one study, based upon self-
report, extending to 21 years (117).
Relapse
Significant consequences to the physician and the public can result from relapse.
PHPs have developed models of assessing relapse severity. DuPont et al. (30)
describe a three-category system derived from the earlier work of one of the
authors (Skipper):
Level I relapse consisted of missing therapy meetings, support groups,

dishonesty, or other behavioral infractions.
Level II relapse involved the reuse of substances but outside the context of
medical practice.
Level III relapse includes substance use within the context of practice.
This relapse system highlights the most frequent downhill slide for professionals
in a monitoring system: problems with recovery maintenance precede substance
use. This helps a PHP stage its interventions prior to substance use. The
downside of this classification system is that a level I “relapse” obfuscates a
commonly accepted term (relapse) and might be better described as a
compliance failure. Thus, this particular relapse classification should be seen as
unique to monitoring programs.
Hankes (reported in Domino et al. (80)) has developed a more extensive
relapse management decision tree for the Washington State PHP that classifies
relapse and provides decision support for managing seven distinct categories of
relapse. It is common for physicians in the first year after treatment to have a
brief relapse or slip. If the slip is short-lived, the physician is often best placed in
short-term relapse prevention programming. Here, the antecedents of substance
use are explored and relapse prevention skills are strengthened. It is not
uncommon for deeper or earlier life issues to emerge during this time as well.
Slips (and the resultant treatment), if managed quickly with appropriate
psychotherapy, can deepen the physicians’ acceptance of their disease and
solidify subsequent recovery. If managed properly, singular slips are most often
helpful in the long run and are not indicators of failed treatment (134). Should a
physician have a more extended relapse, he or she should have a more
comprehensive disease management response including one or more of the
following:
Evaluation of the physician’s safety to practice until he or she is more stable

in recovery
Longer and tighter monitoring contract that includes behavioral monitoring,
support group attendance, and more extensive toxicology testing
Reexamination of the patient’s psychiatric status, to determine whether an
as yet undiagnosed co-occurring psychiatric disorder, other addictive
process, or past unaddressed trauma is present
Reassessment of the patient’s family dynamics and support system
Determination of the need to return to a higher level of care (ASAM Level
2.1, 2.5, 3.1, or 3.5)
Reevaluation of the need for relapse prevention medications
Relapse is part of the disease of addiction. Because of real (and at times
imagined) concerns about patient safety, physicians who have difficulty
maintaining abstinence should be removed from the workforce until evaluators
skilled in physician addiction determine that the physician is safe to return. The
point in time when a physician is safe to practice is best established by a joint
decision of the physician’s treatment provider and the monitoring PHP. All
stakeholders must be prudent and err on the side of caution when considering
readiness to return to work in safety-sensitive occupations. Like it or not, the
stability of an entire state PHP can rest on the outcome of a few highly visible
cases.
Return to Work
Most PHPs insist on an initial removal from the workplace during the first
phases of treatment and after any sustained relapse. The point in time when a
physician is safe to practice is best established by a joint decision of the
physician’s treatment provider and the monitoring PHP. All stakeholders must be
prudent about when to return physicians to their safety-sensitive occupations.
Parameters to consider when returning a physician to his safety-sensitive
occupation are reviewed in Table 49-4. In many cases, it is crucial to address
conditioned cues in the work environment (70,135).
TABLE 49-4 Factors to Review When Considering

Returning a Physician with a Substance Use Disorder to
Work
PHPs and treatment providers have a wide variety of thoughts on how to
structure the physician’s work and home life once a return to work date has been
determined. Issues to be considered include workplace conditions, physician’s
initial workload and whether shift work with rotating time frames should be
allowed, his or her safety to practice around addicting substances, whether solo
or group practice should be considered, any restrictions on prescribing DEA
scheduled drugs, and the need for remedial training. In an effort to increase
consensus on this topic, an instrument called the Medical Professional Addiction
Recovery Inventory has been developed to balance recovery status and the
workplace environment (136).
Treatment Outcome Data

Physicians have been the subject of multiple outcome studies focused on the
efficacy of extended, multimodal addiction treatment and monitoring. Most
addiction treatment outcome studies are plagued by subjects being lost to follow-
up. However, owing to the tight monitoring of PHPs, physician-based studies
have excellent follow-up rates, approximating 90% in some studies (113).
Physicians appear to have responded very well to their unique treatment and
monitoring process. More sophisticated outcome analyses (42,50,80,113,114)
attempt to define why physician treatment is so successful. The natural
progression of this line of thought is to identify which components of the
physician treatment process can be generalized to the public at large (134).
Gallegos et al. (137) reported a 77% sustained abstinence rate in physicians
followed for 5 years. In the North Carolina PHP, Ganley et al. (138) noted 65%
of physicians had a good outcome (as defined by completing an aftercare
contract), and another 26% had a good outcome with complications (eg, relapsed
but eventually completed a monitoring contract) in a 6-year study from 1995 to
2000, resulting in a 91% good outcome. In 2002, Lloyd (117) reported an
impressive follow-up of physicians with alcohol-dependence in the United
Kingdom over 21 years, noting a mean sustained duration of abstinence of 17.6
years in 68 of 80 physicians reporting. He conservatively scored the 20% lost to
follow-up as negative outcomes, and even with this, he noted that 73% of the
physicians in his study of 80 physicians were in recovery. Domino et al. (80)
noted that 25% of physicians in the Washington State PHP (1991 to 2001) had at
least one relapse. Family history, comorbid psychiatric disorder, and a previous
relapse increased the probability of relapse. The use of major opioids increased
the probability of relapse but only in the presence of a comorbid psychiatric
disorder. McLellan et al. (50) evaluated the outcomes among 904 addicted
physicians treated in 16 PHPs and found 78% were continuously abstinent
throughout the 5- to 7-year period of evaluation; more than 90% of those
physicians were still practicing medicine. Among those physicians who did
relapse, 74% had only one episode of substance use.
CONTROVERSIES
Conflicts between Privacy and Public Safety
Physician treatment with its mandated abstinence monitoring illustrates the
conflict between the physician–patient’s need for privacy and the public’s need
for safety. Added to this is a stigmatized view of addiction; the result is that the
addicted physician has become the “whipping boy” of physician impairment.
Many other problems among physicians can and do lead to mistakes and patient
harm (eg, sleep deprivation, overwork, poor communication with hospital staff,
intemperate affairs), but they are not as directly addressed and do not receive a
fraction of the public or regulatory board outcry or concern. Ironically,
confidentiality for treatment of physician mental illness, including substance use
disorders, actually increases patient safety by encouraging early referral and safe
passage into treatment (122,123). During the first several years of implementing
a state PHP, the new program commonly sees a flood of early participants who
are identified by colleagues or family due to the privacy afforded by the PHP.
Conversely, many states have laws that mandate caregivers to report
suspected physician impairment (a term that is not synonymous with addiction
but is often confused as such—more accurately stated—impairment is a
consequence of addiction if it is left untreated). Some states mandate that
treatment providers report physicians to the medical board, regardless of whether
impairment has been proven. In many cases, a default board action ensues.
Although this may appear on superficial examination to protect patients, an
excessively broad mandate for reporting actually decreases the probability that a
physician will seek or accept a referral for assessment and treatment. If the
perceived consequences of referral are sufficiently prejudicial, referral is delayed
and ultimately only occurs when a major incident signals the transition from
illness to impairment. In states with PHPs, regulatory boards allow PHP
intercession, holding off disciplinary proceedings if the physician effectively
addresses his disease in an appropriate, structured, and accountable manner. As
soon as regulatory boards tilt toward law enforcement and away from treatment,
physicians who develop addiction, their colleagues, and care providers become
reluctant to report. The physician with addiction and his or her family delay or
avoid treatment. An uninformed provider may hide behind the confidentiality of
their profession and lose the benefit of the organized monitoring and peer
support provided by a PHP.
The structure of PHPs, on the other hand, facilitates a proper balance
between the privacy that is critical for treatment and the public’s need for safety.
They hold the awkward middle ground between their medical board and
treatment providers. PHPs provide confidentiality if the physician’s illness does
not pose a threat to public safety but report to the medical board should a patient
become uncooperative or a risk to the public at large. The promise of protected
and effective treatment encourages all parties to refer to the PHP before the
physician who uses substances deteriorates to the point of a potential safety risk.
Complaints about Coercion and Control

As with other areas in medicine, concerns have been expressed by the public, the
media, and others that conflicts of interest could compromise decision-making
and undermine the availability, utilization, and reputation of PHPs. Boyd and
Knight (139) argued that impressive results do not obviate the need for scrutiny.
Boyd followed this with several commentaries (140,141). Most PHPs address
these needs through external reviews, oversight by their respective Medical
Boards and a Board of Directors with expertise in balancing effective treatment
with ethical care. Their commentary describes other trepidations such as a higher
dose of initial treatment than the general public. Some of these issues appear
valid on the surface but fail to account for the dual roles of PHPs in protecting
the public and unrealistic expectations many oversight bodies place on
physicians, where a minor relapse can result in loss of a job, hospital privileges,
a medical license, or an entire career. Research, albeit limited, as opposed to
opinion points to good outcomes and a high degree of participant satisfaction
(124). However, there is no available research comparing PHP care versus non-
PHP, or less restrictive or expensive care in matched physician populations.
Beginning in 2015, the Federation of State Physician Health Programs (FSPHP)
developed evolving guidelines for state members that address potential conflicts
of interest and national standards of care (142). The FSPHP is working to
standardize best practices among its members (who have varying staffing,
funding, and experience) through scientific exchange and the development of
guidelines that define best practices.
Is Monitored Recovery the Same as Self-

Guided Recovery?
Physicians frequently enter treatment claiming they are there only to protect
their medical license(s). A central goal in such cases is to shift the physician
from this external driver to an internalized state of recovery as a lifelong journey.
During treatment and subsequent monitoring, a number of physicians do not
make this shift. Once the initial ravages of addiction remit, such individuals are
held in a drug-free state by the oversight of drug screens and behavioral
monitoring. In such cases, the internalization of recovery (an ongoing process of
changing behaviors, attitudes, and beliefs) slows or stops; the transition into the
self-motivated journey of recovery does not replace the holding cell provided by
monitoring. The term disease stasis syndrome has been applied to this small
subset of physicians. Such physicians have a high probability of returning to
substance use, when and if monitoring is discontinued. In the disease stasis
syndrome, the individual has made a commitment to abstinence only as a
temporary means to an end. Such physicians may be quite compliant, assuming a
false persona of acceptance to treatment providers, monitors, and PHP personnel.
Unfortunately, disease stasis is a by-product of external pressure and the
intense treatment and monitoring that physicians undergo. Treatment providers
should avoid pressuring patients to conform because physicians are, after all,
good students who know how to give “correct” answers. Instead, providers
should encourage patients to verbalize their resistance and dissatisfaction with
treatment and to praise honest self-disclosure, especially when the participant is
describing how he or she is stuck in the process of change. Physician–patients
should be encouraged to disclose remnants of the central fallacy of the addicted
mind: the fantasy that they may return to drinking or using drugs in a controlled
and sociable manner once they are “strong enough” or have “learned enough
about myself.” Open discussion regarding recovery ambivalence should be a
recurrent theme in group therapy with this population.
Psychodynamic psychotherapy may help such individuals integrate how past
survival techniques of false compliance to authority figures are at play in their
relationship with the current authority figures, including their therapists,
treatment centers, and PHPs (143). In the meantime, monitoring holds the
physician behaviorally accountable and, if properly framed as appropriate
supportive care, is not only justifiable but also a good medicine. In their
treatment, individuals with the disease stasis syndrome should remain on random
screens, until this syndrome improves. Some cases may need to remain on
screens for an indefinite time.
Merlo and DuPont have completed a preliminary study that attempts to
differentiate between stasis and recovery, to wit: What happens after PHP
monitoring is discontinued? Working with several PHPs, they contacted
individuals at 5 or more years after they completed PHP monitoring. Of 139
anonymous respondents, 95% (n = 121) self-reported no illicit or nonmedical use
of drugs since PHP completion (144). If validated by additional research, these
data suggest that the extended treatment and disease monitoring process in this
cohort create lasting change and not just temporary interruption of the addiction
illness.
Should Physicians Receiving Opioid Agonist

Treatment Return to Practice?
All addiction treatment programs in the United States that specialize in
physicians see discontinuation of opioid agonist treatment as the most desirous
end goal of treatment for opioid use disorder in most cases (30). Most, but not
all, state PHPs also consider the use of opioid agonist and partial agonist
medications carefully and avoid their routine use; this stands in contrast to the
standard of care in the general population. Four issues come into play with this
decision.
First, despite their widespread use, the research on their effects on cognition,
insight, and emotional integration are unclear. Like any CNS-active medication,
buprenorphine and methadone have the potential to affect cognition. Both
decrease delayed recall (especially due to intrusion errors) and decrease
sustained attention, especially in older adults (145). There are suggestions that
even after maintenance has been established, methadone, but not buprenorphine,
affects attention during driving simulation tests as well (146). While the effect
size may not in itself be large, concerns remain. Hamza and Bryson (75)
reviewed the current literature, concluding that cognitive changes of
indeterminate consequence do occur.
Second, public perception of safety is central to an efficient medical system.
Addiction still has a negative connotation in society, and maintenance opioids
(more so with methadone than buprenorphine) draw attention to a physician’s
recovery: a recovery that is never as private and protected as the general public.
Concerns exist in other safety-sensitive industries as well. Pilots cannot fly
airplanes (commercial or private) if they are taking methadone or buprenorphine
(147). Although consensus is shifting, commercial driver’s licenses may be
denied to individuals on opioid treatment medications. The malpractice industry
is one type of public attention physicians avoid at all cost; maintenance opioids
open the door to medical–legal issues. Gray (Gray R, Personal communication,
2007) states, “At least one major statewide malpractice carrier has indicated that
they will not insure an addicted physician if he is on opioid maintenance therapy,
due to the difficulties in defending such a physician in a malpractice case.” Like
it or not, our management of addiction among physicians is modified by public
opinion. It is temerarious to try to educate the public to become more open-
minded about opioid agonist therapy among physicians in the current climate of
oft misguided and injudicious scrutiny.
Third, current screening technology cannot monitor dosage adherence to
agonist medications.
Fourth, and most important, physicians with opioid use disorder have the
same sustained success rates when compared to physicians addicted to other
substances (50,80,113,114,137) when agonist and partial agonist medications are
not used. This stands in sharp contrast outcome studies in the population at large.
Thus, from this efficacy perspective, the use of buprenorphine or methadone is
unnecessary in the majority of physician cases. Said another way, the high
success rates reported in the PHP literature render long-term agonist and mixed
agonist/antagonist medications unnecessary in the majority of cases.
Despite these general statements, exceptions make sense when based on
clinical need. Opioid agonist treatment does occur in the treatment of physicians,
but there is no clear consensus on which cases should be treated with opioid
agonists (or partial agonists). An earlier study of 904 physicians from 16 PHPs
(50) reported that only 1 physician was reported to be receiving opioid agonist
treatment. Skipper (Skipper GE, Personal communication, 2008) surveyed PHPs
and reported that 14 of the 36 PHP who responded indicated they were following
up at least one physician receiving opioid agonist treatment.
This issue becomes more complex when one considers cases of physicians
with opioid use disorder who have chronic, nonmalignant pain. Opioids may be
necessary to maintain the quality of life in such an individual. However, that
same individual may have a history of inappropriate opioid use or even opioid
diversion. In this case, the PHP and treatment providers are balancing the
physician’s need for pain control with the safety of the public and, importantly,
the fear of reprisal by an uninformed public. The decision about a physician’s
ability to practice in such situations should be approached with caution and a
complete knowledge of the research and clinical knowledge in this area.
Although the use of chronic opioids may be necessary in such cases, loss of
control from prescribed doses does occur. The resolution of this conundrum
should rest upon the effect the medication has on the brain and behavior of
physicians who take such medications, not upon the disease for which they are
prescribed. It must be stated, however, that the public and regulatory agencies
are far more tolerant of opioids for analgesia than they are for the treatment of
opioid use disorder.
A second conundrum occurs in the small percentage of physicians with
opioid use disorder who are unable to maintain abstinence from illicit drug use.
In such cases, should physicians be treated using opioid agonist treatment with
methadone or buprenorphine? Different PHPs approach this controversy from
different angles. A few approve the use of opioid agonist treatment in practicing
physicians. In such states, the PHP collaborates with care providers in deciding
who is a proper candidate. Other states strongly oppose the use of opioids,
mostly due to concerns of how it might affect their program as a whole. Still
other states see opioid agonist treatment as a last resort and follow such cases
carefully and/or limit that physician’s scope of practice to mitigate real or
perceived danger. No published studies have addressed this issue to date.
Re-entry of Physicians Diagnosed With

Opioid Use Disorders
Multiple conflicting publications debate the advisability of anesthesiologists and
other physicians who both misused and have high opioid access returning to the
operating room or other arena of high access. Menk et al. (148) reported a
successful re-entry rate of only 34% for parenteral anesthesiologists using
opioids versus 70% for not using opioids. This oft-quoted 1990 study
promulgated a pessimistic view of anesthesiologists returning to work but has
been criticized because it was essentially a retrospective survey of anesthesia
training directors, subject to recall bias. Of the 159 anesthesia training programs
surveyed, 113 responded, providing 180 case reports, with most programs
providing only a single case report of a resident having been addicted. Critics
contend that if most programs reported only a single case, it is likely that such
reports were skewed toward disasters. Collins et al. (149) also surveyed
anesthesiology residencies in 2001, noting that 50% of treated anesthesiologists
remained in anesthesiology after treatment, with 91% completing training and
9% dying of relapse-related incidents.
Paris and Canavan (150) compared 32 anesthesiologists with 36 physician
controls for an average of 7.5 years; they showed no difference in the relapse
rates between these two groups. When stratified by residents versus attending
physicians, no significant difference was found. Domino et al. (80) examined the
risk of relapse over 11 years and 256 participants in a Washington State PHP,
including 32 anesthesiologists. The relapse rate for anesthesiologists was not
statistically significantly different from other physicians. Additionally, there was
not a single episode of patient harm or death from overdose by any
anesthesiologist in this study. A similar report from Pelton and Ikeda (40)
involving 255 physicians who had participated in the California Diversion
Program over 10 years showed no difference in relapse rates for
anesthesiologists.
Domino et al. (80), evaluating physicians in the Washington State PHP,
noted that physicians who had used fentanyl had a slightly lower incidence of
relapse than those who had used other major opioids. Individuals who used
potent opioids (excluding fentanyl) had a higher risk of relapse as did physicians
with an existing comorbid psychiatric disorder or a family history of addiction.
They conclude that anesthesiologists who used potent opioids and do not have
other risk factors (family history, comorbid psychiatric disorder, and history of
relapse) are good candidates to return to the practice of anesthesiology. A more
recent study by Skipper (114) reviewed data from PHPs in 16 states, culling
information about anesthesia providers. They noted that anesthesiologists had
outcomes similar to other physicians, with no higher mortality, relapse rate, or
disciplinary rate and no evidence in their records of patient harm. These authors
postulated that the type of treatment and monitoring that these physicians
received from the 16 state PHPs accounts for the differences from earlier reports.
Oreskovich and Caldeiro imply there are two approaches to managing opioid
addiction among anesthesiologists (151). One, more common early on, involves
low-dose initial treatment and minimal or noncomprehensive drug screening and
medication assistance. The second is composed of aggressive treatment and
long-term oversight, has sophisticated hair and nail testing for fentanyl, and
involves placement on depot naltrexone. These authors purport that the literature
supports the latter construct. Studies that followed anesthesiologists under close
monitoring in PHPs or by regulatory boards (Domino (80),Washington State;
Paris and Canavan (150), New Jersey; Pelton and Ikeda (40), California; Skipper
(114), 16 different states with active PHPs) describe outcomes for
anesthesiologists that are similar to other physicians, whereas earlier studies that
are based upon a survey of the memories of anesthesiology program directors
(where patients had uncertain or limited treatment and monitoring) describe
poor, and at times, life-terminating outcomes. The controversy about returning
anesthesiologists to practice underscores the importance of sophisticated PHPs
in maintaining recovery for their participants and ensuring public safety.
Several studies point to the importance of opioid antagonists in the long-term
management of the anesthesiologist with opioid use disorder. Merlo et al. (119)
in a naturalistic crossover study in one PHP showed the risk of relapse on
opioids was significantly decreased when physicians who used parenteral
opioids are given injectable naltrexone upon initial return to a high-risk practice
environment. Many providers working with this cohort suspect that exposure to
conditioned environmental cues while protected by naltrexone diminishes
conditioned cue craving (70).
What Happens when a Physician Relapses?

Addiction is often characterized by periods of abstinence alternating with
relapse. In contrast, the expectation by medical boards and the public is that
physicians should never relapse, placing another burden of perfectionism upon a
cohort who are already perfectionist and harshly self-critical. For some
physicians, the experience of recovery feels more like a jail of perfectionism
instead of a journey where one learns to accept imperfections. The consequence
of relapse for any person with addiction entails a loss of self-efficacy. For the
physician, it may involve a loss of livelihood and facing possible board or legal
sanctions.
Physicians early in their recovery often experience a brief “discovery”
relapse (a return to drug use where the individual’s relapse experience validates
and internalizes a heretofore poorly accepted diagnosis) (80,152). PHPs are
familiar with such occurrences; medical boards and the public at large are not.
Research into, and standardization of, interventions in the event of an early
recovery relapse should improve outcomes and at the same time increase public
trust.
Repeated relapses that run the risk of public harm should be managed by
removing such an individual from his or her practice. Physicians who experience
multiple relapses may need a sustained period of remission prior to a return to
practice. Involvement in support systems and length of remission predict the best
prognosis moving forward (153).
CONCLUSION
Physicians were the first professional group to address addiction within their
profession; this leadership continues today. The disease of addiction in
physicians follows a similar course as in the public at large, with several notable
exceptions. The access to potent drugs is one of the most important of these
exceptions. The identification, evaluation, initial treatment, and subsequent
addiction monitoring in this population may afford useful elements of disease
management that can be adapted to the treatment of addiction in the public at
large (134).
The treatment of physicians is different (especially in the United States),
partly driven by public outcry for complete and sustained remission in a disease
that is chronic and relapsing by nature. PHPs remain integral elements in the
comprehensive disease management of physician addiction. Controversies in the
management of addiction in physicians abound and call for further research in
this interesting and complex population.
The California Diversion Program: A
Cautionary Tale
In 1978, the California Board of Medical Quality Assurance (BMQA)
developed a Diversion Program to assist physicians with alcohol and drug
problems, “diverting” them from disciplinary action if they followed the
requirements of the program. Authorizing legislation was passed in 1979 and
the program opened on January 1, 1980. The participation of physicians who
entered the program was not publicly disclosed. In the ensuing 27 years, up to
350 physicians at a time were managed in the Diversion Program. Even at its
peak, the Diversion Program monitored only 0.47% of licensed physicians in
the state. As part of a standard oversight process required by the state, the
program underwent audits every few years.
At first, the audits were conducted by a state agency. In 2003, a consumer
group, the Center for Public Interest Law (CPIL) (154), was approved to be the
auditor of the Diversion Program. These audits were more critical, eventually
alleging that several physicians had harmed patients. Stories appeared in
newspapers; one example was about a “diversion-protected” physician who
used drugs, who in fact had been dropped from the Diversion Program for
failure to comply with program requirements. He had previously been turned
over to the disciplinary arm of the California Medical Board. Hearings were
held where CPIL speakers repeated their opinion that keeping names of the
physicians in the Diversion Program from the public was contrary to the public
protection mission of the Medical Board of California.
Legislation required the board to complete a semiyearly renewal
authorization for the Diversion Program. In 2007, the MBC voted unanimously
to deny renewal, under tremendous pressure from the CPIL, the media, and
some legislators. The program was closed on June 30, 2008. In response to a
gaping hole in physician monitoring, local medical societies and hospital
systems attempted to continue to provide such services. This makeshift
approach continues to this day.
Reacting quickly, the California Medical Association (CMA), California
Hospital Association (CHA), California Society of Addiction Medicine
(CSAM), California Psychiatric Association (CPA), the University of
California, California’s malpractice liability insurance carriers, providers of
care, and others came together to promote legislation to rebuild a PHP in
California. In 2009, the resultant work group created a new 501(c)(3)
organization, California Public Protection and Physician Health, Inc (CPPPH),
independent of its parents. Its work ever since has been to further assist the
parent organizations prepare for a full state-sanctioned PHP and to promote
physician health (155).
After five attempts and thousands of man-hours, legislation was finally
passed to repair the system for providers and patient safety. At the time of this
writing, the Medical Board is writing regulations to govern the new
organization.
Many lessons come from this cautionary tale. First, even though the duty of
PHPs is the health and safety of all, they are sustained or destroyed by public
opinion and politics. Second, physicians are safety-sensitive workers and are
appropriately held to a higher standard. Effective treatment and monitoring
decreases but does not eliminate public fear, even though it does not have a
basis in reality. Third, the outcome of a few physicians can affect the entire
organization—even after being ejected from the safe haven of a PHP and turned
over to disciplinary bodies.
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SECTION 6
Management of Intoxication and

Withdrawal
CHAPTER 50
Management of Intoxication and
Withdrawal: General Principles
Tara M. Wright, Jeffrey S. Cluver and Hugh Myrick
CHAPTER OUTLINE
Introduction
Intoxication States
Recognizing the Impact of Ever Changing Drug Trends
Withdrawal States
Special Populations
Conclusions
INTRODUCTION
Recognition of intoxication and withdrawal states is critical for the appropriate
management of individuals with substance use disorders. In addition to being
able to recognize the unique intoxication and withdrawal states of particular
substances, the treatment of patients who are under the influence of, or
experiencing withdrawal from, substances requires an understanding of many
variables. These variables include an appreciation of the natural history and
variants of such syndromes, a complete assessment of the patient’s individual
medical, psychiatric, and social issues, and knowledge of the uses and
limitations of a variety of behavioral and pharmacological interventions. All
therapies must be individualized to each patient’s needs and adjusted to reflect
the patient’s response to treatment.
The number of referrals to emergency departments (EDs) due to
complications from acute intoxication or withdrawal states remains at all-time
highs. Data from the Drug Abuse Warning Network revealed that the total
number of drug-related ED visits increased from 2004 (626 470 visits) through
2011 (1 428 145 visits). In regard to pharmaceuticals, the most commonly
involved were opioid analgesics and sedative–hypnotics (1). While
pharmaceuticals continue to be involved at a higher rate than illicit drugs,
findings of the DAWN 2011 revealed an increase in the involvement of illicit
drugs. Between 2009 and 2011, the rate of visits involving illicit stimulants
increased 68%, and the rate of visits involving marijuana rose 19% (1). Drug
overdose is now the leading cause of accidental death in the United States, with
55 403 lethal drug overdoses in 2015. Opioid use disorders are driving this
epidemic, with 20 101 overdose deaths related to prescription pain relievers and
12 990 overdose deaths related to heroin in 2015 (2). In addition, it is imperative
to differentiate between those emergent visits involving a single drug and those
involving multiple drugs. Among opioid analgesic-related ED visits involving
nonmedical use that occurred in 2011, only 44% involved opioid pain relievers
solely. In the remaining 56% of these visits, additional drugs were involved, the
most common other pharmaceutical class involved being benzodiazepines (3).
This chapter serves as an introduction to the identification and management
of intoxication and withdrawal states, with the management of specific
substances to be reviewed in subsequent chapters in this section.
INTOXICATION STATES
Intoxication is the result of being under the influence of, and responding to, the
acute effects of alcohol or another drug. It typically includes feelings of pleasure,
altered emotional responsiveness, altered perception, and impaired judgment and
performance. The recognition of intoxication states is of paramount importance
in the appropriate treatment of substance-using patients. Intoxication states can
range from euphoria or sedation to life-threatening emergencies when overdose
occurs. Typically, each substance has a set of signs and symptoms that are seen
during intoxication. Identification and treatment of intoxication can lead to
appropriate management of the withdrawal phenomenon and provide an avenue
for entry into treatment. The initial challenge to the clinician, however, is
diagnosis, because intoxication can mimic many psychiatric and medical
conditions.
Identification and Management of

Intoxication
The identification of intoxication begins with the collection of patient data
through a patient history, physical examination, and laboratory screening. Of
immediate concern is life-threatening intoxication or overdose. Thus, the first
priority is general supportive care and resuscitative actions. It is important to
determine not only the severity of the substance ingestion but also the patient’s
level of consciousness, the substances involved, and any complicating medical
disorders. Often, more than one substance is involved, and it is critical to know
what substances have been ingested, as well as how much of each substance.
Historical information regarding substance use usually can be obtained from
the patient. Questions regarding the quantity and frequency of substance use
provide valuable information to the clinician. Discovering chronic patterns of
substance use may aid in subsequent referral to addiction treatment. Acute
intoxication may impede an individual’s ability to provide such information. In
these cases, the patient’s companions or family may be able to provide important
information.
Standardized questionnaires for self-administration by the patient or for use
by the clinician are designed to elicit answers related to alcohol or substance use.
Toxicology screens provide valuable information regarding the type or types of
substances used. When screening for substances used, urine is the most widely
used specimen because of the ease with which a sample is obtained, the
relatively high concentrations of drugs and metabolites present in urine, and the
stability of metabolites when frozen. Drug testing can aid in the differential
diagnosis when atypical symptoms are present. Such testing can be particularly
helpful in cases where little clinical history is available. Having knowledge of
the sensitivities, specificities, and cross-reactivities of the particular urine drug
test being used is of vital importance to the appropriate interpretation. In
addition, one must have an understanding of the usual duration of detectability
of particular substances. However, the duration of detectability can be
significantly impacted by the amount of substance ingested, individual rates of
metabolism and excretion, as well as fluid ingestion of the individual. It is
equally important to note that the rise in the use of synthetic or “designer” drugs
can make identification of the causative substance(s) more difficult, as these
substances are frequently not detected by routine toxicology testing.
Testing for alcohol is most frequently accomplished by breathalyzer or blood
alcohol levels; however, urine tests are also available that detect metabolites of
alcohol. Laboratory assays that measure increases in liver enzymes—such as
gamma-glutamyl transferase, aspartate aminotransferase, and alanine
aminotransferase—can be helpful in indicating possible heavy alcohol use.
Although alcohol is not the only cause of an increase in gamma-glutamyl
transpeptidase (GGT), and GGT frequently does not increase in younger
drinkers, this assay may help clinicians consider that the patient may be drinking
alcohol excessively. A biological assay to monitor alcohol intake involves
percent carbohydrate-deficient transferrin (%CDT), a more sensitive and specific
indicator of heavy alcohol consumption (4). The conjugated ethanol metabolites
ethyl glucuronide (EtG) and ethyl sulfate (EtS) are other measures that can also
be used to confirm or rule out recent drinking. Although EtG and EtS account
for only <0.1% of the ingested ethanol dose, they remain detectable in urine for
several hours up to some days longer than ethanol, the time lag largely
depending on the amount consumed (5). Another biomarker is serum-based
phosphatidyl ethanol (PEth), which may be able to detect the presence of even a
few days of heavy alcohol consumption for as long as 3 weeks after (4).
RECOGNIZING THE IMPACT OF EVER

CHANGING DRUG TRENDS
Trends in substance use are ever changing as new drugs often burst on the scene
rapidly. As many of these drugs are synthetic and may not be detected in the
routine drug testing, it is imperative that the treating clinician keep abreast of
recent trends in their geographical area. At the time of this writing, there has
been a stark rise in the use of heroin as well as designer synthetic opioids, in
large part related to the decline in accessibility and rising street cost of
prescription opioid analgesics. To that end, the National Institute on Drug Abuse
(NIDA) launched the National Drug Early Warning System (NDEWS) in August
2014 to create a national network in the identification and monitoring of
emerging drug problems.
WITHDRAWAL STATES
Substance withdrawal has been defined by the American Psychiatric Association
as “the development of a substance-specific maladaptive behavioral change,
usually with uncomfortable physiological and cognitive consequences, that is the
result of a cessation of, or reduction in, heavy and prolonged substance use” (5).
The signs and symptoms of withdrawal usually are the opposite of a substance’s
direct pharmacological effects. Substances in a given pharmacological class
produce similar withdrawal syndromes; however, the onset, duration, and
intensity are variable, depending on the particular agent used, the duration of
use, and the degree of neuroadaptation.
Evidence for the cessation of or reduction in use of a substance may be
obtained by history or toxicology. Additionally, the clinical picture must not be
solely attributable to other medical conditions or a primary mental disorder (5).
Withdrawal may, however, be superimposed on any medical condition or organic
mental disorder. Therefore, a thorough physical examination is necessary,
including appropriate laboratory analysis of basic organ functions.
The term detoxification implies a clearing of toxins. The process of
providing detoxification can also be termed medically supervised withdrawal.
Detoxification, or medically supervised withdrawal, is defined as the
management of the substance’s withdrawal syndrome.
Goals of Detoxification
Detoxification includes a set of interventions by which a substance an individual
is physically dependent on is eliminated from the body. Detoxification seeks to
minimize the physical harm caused by the use of substances. The American
Society of Addiction Medicine (ASAM) lists three immediate goals for
detoxification of alcohol and other substances: (a) “to provide a safe withdrawal
from the drug(s) of dependence and enable the patient to become drug-free,” (b)
“to provide a withdrawal that is humane and thus protects the patient’s dignity,”
and (c) “to prepare the patient for ongoing treatment of his or her dependence on
alcohol or other drugs” (6). Furthermore, it comprises three essential and
sequential steps: evaluation, stabilization, and fostering patient readiness for and
entry into treatment (7). It is important to distinguish detoxification from
substance use disorder treatment. Substance use disorder
treatment/rehabilitation involves a constellation of ongoing therapeutic services
ultimately intended to promote recovery for substance use disorder patients (7).
Detoxification may be the first step in this process.
Many risks are associated with substance use withdrawal, some of which are
influenced by the setting in which detoxification occurs. For example, in persons
who are severely physically dependent on alcohol, an abrupt, untreated cessation
of drinking may result in marked hyperautonomic signs, seizures (which may be
recurrent), withdrawal delirium, or even death. Other sedative–hypnotics also
can produce life-threatening withdrawal syndromes. Withdrawal from opioids
and stimulants produces severe discomfort, but generally is not life-threatening.
It may, however, present a danger to those who are debilitated by advanced HIV
disease, medical sequelae of addiction, advanced age, coronary artery disease,
and other medical problems. Moreover, risks to the patient and society are not
limited to the severity of the patient’s physical disturbance, particularly when the
detoxification is conducted in an outpatient setting. Outpatients experiencing
withdrawal symptoms may self-medicate with alcohol or other drugs that can
interact with withdrawal medications in an additive fashion or precipitate
overdose.
A caring staff, a supportive environment, sensitivity to cultural issues,
confidentiality, and the selection of appropriate detoxification medications (as
needed) are important components of a humane withdrawal. However, staff must
be clear in their treatment goals and set firm boundaries, as well as be
sympathetic and have experience in dealing with difficult behaviors that often
accompany detoxification. Supportive others (family members, friends, or
employers) should be enlisted whenever possible to assist in the care of the
patient during outpatient detoxification.
During detoxification, patients may form therapeutic relationships with
treatment staff and other patients, providing an opportunity to explore
alternatives to an alcohol- or drug-using lifestyle. Detoxification is therefore an
opportunity to offer patients information and to motivate them for longer-term
treatment. Unfortunately, managed care organizations and other third-party
payers often regard detoxification as separate from other phases of alcohol and
other drug treatment, as though detoxification occurs in isolation from such
treatment. In clinical practice, this separation should not exist; detoxification is
but one component of a comprehensive treatment strategy.
General Principles of Management

Some detoxification procedures are specific to particular drugs, whereas others
are based on general principles of treatment and are not drug specific. The
general principles are presented here; subsequent chapters address specific
treatment protocols for each class of drugs.
There is a risk of serious adverse consequences for some patients who
undergo withdrawal. As such, an initial medical assessment is important to
determine the need for medication and medical management. Such an
assessment should include evaluation of predicted withdrawal severity and
medical or psychiatric comorbidity. Although the severity of a given patient’s
withdrawal cannot always be predicted with accuracy, helpful information
includes the amount and duration of alcohol or other drug use, the severity of the
patient’s prior withdrawal experiences (if any), and the patient’s medical and
psychiatric history. Past complicated withdrawal should alert the practitioner to
the likely possibility of future complicated withdrawals. The kindling hypothesis
has been well supported in alcohol research, such that past alcohol withdrawal
seizures are a strong indicator of future alcohol withdrawal seizures (8). A
widely used instrument in clinical and research settings for the initial assessment
and ongoing monitoring of alcohol withdrawal is the Clinical Institute
Withdrawal Assessment-Alcohol, revised (CIWA-Ar. The Clinical Institute
Withdrawal Assessment-Alcohol, revised is a short test that rates the severity of
withdrawal, as observed by the clinician. In general, low scores (<8) suggest that
pharmacotherapy may not be required, whereas high scores (>10) indicate a
greater risk of alcohol withdrawal syndrome complications. Similarly, the
Clinical Opiate Withdrawal Scale (COWS) is an 11-item scale administered by
the clinician to help determine the stage and severity of opioid withdrawal over
time.
Every means possible should be used to ameliorate the patient’s withdrawal
signs and symptoms. Medication should not be the only component of treatment,
because psychological support is extremely important in reducing the patient’s
distress during detoxification.
The duration of detoxification is not a clearly defined, discrete period.
Because detoxification often requires a greater intensity of services than other
types of treatment, there is a practical value in defining a period during which a
person is “in detoxification.” The detoxification period usually is defined as the
time during which the patient receives detoxification medications, even though
some signs and symptoms may persist for a much longer period. Another way of
defining the detoxification period is by measuring the duration of withdrawal
signs or symptoms. However, the duration of these symptoms may be difficult to
determine in a correctly medicated patient, because symptoms of withdrawal are
largely suppressed by the medication.
Another problem in defining the duration of detoxification is the fact that
many patients may have prolonged withdrawal signs or symptoms, or
“protracted withdrawal syndrome.” Symptoms may include disturbances of
sleep, anxiety, irritability, mood instability, and craving. Despite advances in the
literature elucidating the neurobiology of protracted withdrawal, appropriate
pharmacological management of such requires further exploration. The
protracted withdrawal syndrome is hypothesized to be a period when individuals
are at a heightened risk of relapse (9–11).
Physicians often find it difficult to distinguish symptoms caused by drug
withdrawal from those caused by a patient’s underlying mental disorder, if one is
present. The signs and symptoms of protracted withdrawal are not as predictable
as those of acute withdrawal, which produces measurable signs that researchers
can study in animals under controlled laboratory conditions; protracted
withdrawal, on the other hand, often is confined to distress symptoms for which
there are no adequate animal models. The plan of care for detoxification should
be individualized to account for the considerable variation among patients in
terms of signs and symptoms of withdrawal. The best outcomes are obtained by
tailoring the detoxification regimen to meet the needs of individual patients. The
initial plan of care for detoxification should be adjusted to reflect the patient’s
response to the treatment provided.
Pharmacological Management
There are two general strategies for pharmacological management of
withdrawal: suppressing withdrawal through use of a cross-tolerant medication
and reducing signs and symptoms of withdrawal through alteration of another
neuropharmacological process. Either or both may be used to manage
withdrawal syndromes effectively. To suppress withdrawal with cross-tolerant
medication, a longer-acting medication typically is used to provide a milder,
controlled withdrawal. Examples include use of methadone for opioid
detoxification and diazepam for alcohol detoxification. Medications that are not
cross-tolerant are used to treat specific signs and symptoms of withdrawal.
Examples include use of clonidine for opioid or alcohol withdrawal.
Detoxification alone rarely constitutes adequate treatment. The provision of
detoxification services without continuing treatment at an appropriate level of
care constitutes less than optimal use of limited resources. The maintenance of
abstinence can be a very difficult goal to achieve: it has been estimated that
~50% of patients with alcohol use disorder relapse within 3 months of
detoxification. The appropriate level of care and content of treatment following
detoxification must be clinically determined, based on the patient’s individual
needs. ASAM’s criteria are the most widely used and comprehensive set of
guidelines used for determining the appropriate level of care for a patient within
the continuum of addiction services. Using the criteria, levels of treatment are
differentiated based on (a) degree of direct medical management provided; (b)
degree of structure, safety, and security provided; and (c) degree of treatment
intensity provided (12).
Detoxification Settings
The initial assessment should facilitate the selection of the appropriate level of
care for detoxification. In determining the most appropriate setting, the
practitioner should match the patient’s clinical needs with the least restrictive
and most cost-effective setting (7). Detoxification may take place in a variety of
inpatient and outpatient settings. Multiple instruments have been designed to
facilitate selection of an appropriate level of care. The ASAM Criteria contain
detailed guidelines for matching patients to an appropriate intensity of services
for detoxification. Detoxification is conducted in both inpatient and outpatient
settings. Both types of settings initiate recovery programs that may include
referrals for problems such as medical, legal, psychiatric, and family issues.
Inpatient Detoxification
Inpatient detoxification is offered in medical hospitals, psychiatric hospitals, and
medically managed residential treatment programs. It allows 24-hour
supervision, observation, and support for patients who are intoxicated or
experiencing withdrawal. The primary emphasis in this setting should be placed
on ensuring that the patient is medically stable (including the initiation and
tapering of medications used for the treatment of substance use withdrawal),
assessing for adequate biopsychosocial stability (and quickly intervening if this
is lacking), and linking the patient to appropriate inpatient and outpatient
services once it is medically safe to do so (7). Inpatient detoxification provides
the safest setting for the treatment of substance withdrawal, because it ensures
that patients will be carefully monitored and appropriately supported. Such
monitoring is especially important if the patient is physically dependent on high
doses of alcohol or other sedative–hypnotic drugs. Compared with outpatient
detoxification, inpatient detoxification may provide better continuity of care for
patients who begin treatment while in the hospital. In addition, inpatient
detoxification separates the patient from substance-related social and
environmental stimuli that might increase the risk of relapse.
In the case of detoxification from alcohol, about 20% of those undergoing
treatment for alcohol withdrawal must be treated as inpatients. Relative
indications for inpatient treatment include past alcohol withdrawal seizures or
delirium, pregnancy, dependence on other substances, older age, medical or
psychiatric illness, or lack of a reliable support system (13). Abnormalities of
electrolytes or blood counts, infection, trauma, and the presence of structural
brain lesions can be predictors of the most severe cases of withdrawal (14,15).
Inpatient care of alcohol withdrawal can be 10-20 times as expensive as
outpatient care. Generally, therefore, it is reserved for those expected to have
severe withdrawal symptoms and to require a more intensive level of care (such
as patients with past severe withdrawal symptoms).
Outpatient Detoxification
Outpatient detoxification usually is offered in community mental health centers,
methadone maintenance programs, addiction treatment programs, and private
clinics. Essential components to a successful outpatient detoxification include a
positive and helpful social support network and regular accessibility to the
treatment provider (7). Medical and nursing personnel involved must be readily
available to evaluate and confirm that detoxification in the less supervised
setting is safe. They must be able to interpret the signs and symptoms of alcohol
and other drug intoxication and withdrawal, have knowledge of the appropriate
treatment and monitoring of these conditions, and have the ability to facilitate
the individual’s entry into treatment (7). Advantages of outpatient detoxification
include the fact that it is much less expensive than inpatient treatment, the
patient’s life is not disrupted to the degree that it is during inpatient treatment,
and the patient does not undergo the abrupt transition from a protected inpatient
setting to the everyday home and work settings.
Emergency departments (EDs) are important components of outpatient
detoxification as they often serve as a gateway to detoxification services.
Detoxification programs may rely on ED staff to assess and initiate treatment for
patients with medical conditions or medical complications that occur during
detoxification. For social model programs, EDs often serve as a safety net for
patients who need medical treatment. For the substance-using individual who
has overdosed or who is experiencing a medical complication of use, the ED
may be the initial point of contact with the healthcare system and serve as a
source of case identification and referral to detoxification. Many patients
experiencing alcohol withdrawal seizures present initially to an ED where they
are taken after a seminal episode.
Considerations in Selecting a Setting

The best detoxification setting for a given patient may be defined as the least
restrictive, least expensive setting in which the goals of detoxification can be
met. The ability to meet this standard assumes that treatment choices always are
based primarily on a patient’s clinical needs. A comprehensive evaluation of the
patient often indicates what therapeutic goals might be achieved realistically
during the time allotted for the detoxification process.
Treatment providers should consider detoxification settings and patient
matching within the context of a fundamental principle of high-quality patient
care. This principle is that the patient’s needs should drive the selection of the
most appropriate setting. The severity of the patient’s withdrawal symptoms and
the intensity of care required to ensure appropriate management of these
symptoms are of primary importance. Pressures to achieve cost savings are
having a significant effect on the selection of treatment settings for
detoxification. Many insurance companies, managed care organizations, and
other payers have adopted stringent policies concerning reimbursement for
alcohol and other drug detoxification services. These policies govern not only
the setting in which the services are provided but also the maximum number and
duration of detoxification episodes that are covered benefits. Such policies give
insufficient weight to the variety of factors that affect the selection of a setting in
which the patient has the greatest likelihood of achieving satisfactory
detoxification. Some persons in need of detoxification, for example, may not be
appropriate candidates for outpatient detoxification because of environmental
impediments such as a spouse who is using alcohol or other drugs. Such a
patient may be more appropriately detoxified in a residential setting such as a
recovery house or other residential environment that is free of alcohol and other
drug use. Panelists convened by the federal Center for Substance Abuse
Treatment expressed concern that important clinical decisions often are driven
by economic rather than clinical considerations (6,7). They affirmed that the
dominant principle in patient placement is that detoxification is cost-effective
only if it is appropriate to the needs of the individual patient.
Use of the ASAM Criteria

The ASAM Criteria are intended for use as a clinical tool for matching patients
to appropriate levels of care. The criteria reflect a clinical consensus of adult and
adolescent treatment specialists and incorporate the results of a comprehensive
peer review by professionals in addiction treatment. They use six dimensions in
the biopsychosocial assessment of individuals needing substance use services.
These dimensions include acute intoxication and/or withdrawal potential;
biomedical conditions and complications; emotional, behavioral, or cognitive
conditions and complications; readiness to change; relapse, continued use, or
continued problem potential; and recovery/living environment. Individual
treatment plans are developed through the multidimensional assessment over
five broad levels of treatment, which are based on the degree of direct medical
management provided; the structure, safety, and security provided; and the
intensity of treatment services provided. The five broad levels of care include
early intervention, outpatient services, intensive outpatient/partial hospitalization
services, residential/inpatient services, and medically managed intensive
inpatient services. In between these broad levels are gradations in intensity of
services (12).
Relapse
Many individuals undergo detoxification more than once, and some do so many
times. When recently physically dependent persons return for repeat
detoxification, it generally is with a more realistic expectation of what is needed
to remain free from alcohol and other drugs. O’Brien et al. (16) point out that
compliance and relapse in addictive disease are comparable to rates of relapse in
other illnesses, such as diabetes and hypertension. Therefore, they recommend
comparable long-term treatment. Although addicted persons are at increased risk
of relapse at certain points in their recovery, relapse can occur at any time. The
relapsed patient is an appropriate candidate for detoxification and continuing
treatment, including relapse prevention education.
SPECIAL POPULATIONS
Although researchers have not yet thoroughly evaluated withdrawal strategies
for certain populations, patients in several groups clearly require special
consideration.
Pregnant and Nursing Women

Special concerns attend detoxification during pregnancy. The teratogenic effects
of alcohol on a fetus are well documented. Progression to severe withdrawal
from alcohol or sedative hypnotics carries a significant mortality to mother and
fetus, so early identification and management are of utmost importance.
Withdrawal/detoxification should be managed in an inpatient setting, which
allows for medical supervision in collaboration with an obstetrician. Although
benzodiazepines may carry risk to the fetus when given during pregnancy, the
risk to both mother and fetus from untreated sedative–hypnotic withdrawal is
considered greater. Therefore, if medical management of withdrawal is
necessary, benzodiazepines are used judiciously.
Withdrawal from opioids can result in fetal distress, which can lead to
premature labor or miscarriage. On the other hand, opioid agonist treatment,
coupled with good prenatal care, is generally associated with good maternal and
fetal outcomes. Methadone maintenance has historically been accepted as the
standard approach to the pregnant woman with opioid use disorder; however,
recent research also supports the efficacy of buprenorphine, particularly as it
may reduce the harms associated with neonatal abstinence syndrome (17,18). It
should be noted, however, that both of these medications are classified as
pregnancy category C (animal studies have shown risk to the fetus, there are no
controlled studies in women, or studies in women and animals are not available).
Although offspring of women on opioid maintenance therapy tend to have a
lower birth weight and smaller head circumference than drug-free newborns, no
developmental differences at 6 months of age have been documented. Clonidine
(frequently used in opioid detoxification) also is a pregnancy category C
medication.
Federal panels recommend that all pregnant and nursing women be advised
of the potential risks of drugs that are excreted in breast milk (6,19).
Nevertheless, they advise that detoxification protocols should not be modified
for nursing women unless there is specific evidence that the detoxification
medication enters the breast milk in amounts that could be harmful to the
nursing infant (6,19). These decisions often must include weighing the risks and
benefits to both the mother and infant. For instance, the American Academy of
Pediatrics (20) categorizes benzodiazepines as “drugs for which the effect on
nursing infants is unknown, but may be of concern.” The addiction provider
should coordinate treatment decisions with an obstetrician or pediatrician in
these cases.
Persons Who Are HIV Positive

Substance use disorders increase the risk of contracting HIV through the use of
contaminated needles and risky sexual behavior. In addition, substance use
disorder treatment can help reduce the transmission of HIV by reducing these
behaviors (21). Substance use disorders and HIV/AIDS interact with one another
in a complex manner. The presence of an alcohol or other drug addiction can
certainly impede adherence with an individual’s medication regimen for the
treatment of HIV (21). A diagnosis of HIV infection does not change the
indications for detoxification medications, which can be used in HIV-positive
persons in the same way they are used in uninfected patients. A federal panel
advises that, if deemed appropriate, the detoxification process need not be
altered by the presence of HIV infection (6,22,23). However, the treatment
provider does need to be aware of the possible drug interactions between
antiretroviral agents used to treat HIV and medications used in detoxification
and adjust dosages accordingly. For instance, methadone and buprenorphine are
two agents widely used in the management of opioid use disorders, both of
which can have interactions with HIV medications, although methadone to a
more significant degree than buprenorphine (24).
Patients With Other Medical Conditions

Neurological Disorders
Brain-injured patients are at risk for seizures (6). If an alcohol- or other drug-
using patient who has sustained trauma to the head becomes delirious, the cause
of the delirium should be investigated. Slower medication tapers should be used
in patients with seizure disorders (6). Doses of anticonvulsant medications
should be stabilized before sedative–hypnotic withdrawal begins. The treatment
of individuals with alcohol or other sedative dependence and past seizures is
controversial largely because of challenges determining whether past
convulsions were substance-related or not. In such a situation, the use of
anticonvulsant agents (carbamazepine, valproate) should be considered, in
combination with benzodiazepines.
Cardiovascular Disorders
Patients with cardiac disease require continued clinical assessment. Underlying
cardiac disease may be worsened by the symptoms of autonomic arousal
(elevated blood pressure, increased pulse, and sweating) as seen in alcohol,
sedative, and opioid withdrawal (7). Because of this, it may be necessary to
withdraw the medication at a slower than normal rate and to consider use of
additional medications such as beta-blockers or clonidine. Treatment providers
also should be alert to the possibility of interactions between cardiac medications
and the agents used to manage detoxification.
Hepatic or Renal Disorders

Severe liver or renal disease can slow the metabolism of both the addictive drug
and the detoxification medication. Use of shorter-acting detoxification
medications and a slower taper is appropriate for such patients but requires
precautions against drug accumulation and oversedation (7).
Chronic Pain
It is well known that chronic pain and addiction frequently co-occur (25).
Neither are static conditions; both fluctuate in intensity overtime and under
different conditions and require ongoing management (26). Treatment for one
condition can support or conflict with treatment for another; but it is clear that
both conditions must be appropriately addressed. Treatment providers must
exercise caution when prescribing medications for chronic pain in patients who
have current or past substance use disorder. In a large secondary data analysis of
persons who have chronically used opioids for chronic noncancer pain, a
diagnosis of non–opioid pre-DSM-5 defined substance abuse (identified by
having at least one visit or inpatient stay with the associated ICD-9-CM code)
was the strongest predictor of an opioid use disorder (27). Mental health
disorders were also moderately strong predictors of opioid use disorder in this
group (27). Furthermore, the use of Schedule II opioids, headache, back pain,
and substance use disorders have been associated with increased ED visits and
alcohol- or drug-related encounters among adults prescribed opioids for 90 days
or more. It may be possible to increase the safety of chronic opioid therapy by
minimizing the prescription of Schedule II opioids in these higher-risk recipients
(28).
General principles when using opioids in the treatment of chronic pain
include comprehensive follow-up, using adjunctive interventions where
necessary, regular prescription pickup, appropriate screening for use and misuse,
and a limitation on the number of physicians and pharmacists providing
treatment (29). In addition, physicians must comply with their state’s medical
board on participating in prescription drug monitoring program. The goal of this
is to monitor both patient and provider behavior; it allows the provider to know
if the patient is receiving other controlled medications from other providers in
the state, dosage, and amount supplied. When indicated, any patient who has
taken opioids or sedative–hypnotics for a prolonged period should be weaned
from them gradually. Furthermore, the best outcomes often come from a
multidisciplinary team, where nonpharmacological treatment is an important part
of the treatment planning (26).
Patients With Psychiatric Comorbidities

It is difficult to accurately assess underlying psychopathology in a patient who is
undergoing detoxification. Drug toxicity or organic psychiatric symptoms
(particularly with amphetamines, cocaine, hallucinogens, or phencyclidine
[PCP]) can mimic psychiatric disorders. For this reason, thorough psychiatric
evaluation should be conducted after 2-3 weeks of abstinence. At the time
patients are evaluated for detoxification, some with underlying psychiatric
disorders already may be prescribed antidepressants, antipsychotics, anxiolytics,
or lithium. Although staff at some treatment programs may believe that such
patients should discontinue all psychoactive medications, a federal panel has
advised that this course of action may not be in the best interest of the patient
(6). Abrupt cessation of psychotherapeutic medications may cause withdrawal
symptoms or reemergence of symptoms of the underlying psychopathology.
Thus, decisions about discontinuing the medication should be deferred
temporarily. If, however, the patient has been misusing the prescribed
medication or the psychiatric condition clearly was caused by the patient’s
alcohol or other drug use, the rationale for discontinuing the medication is more
compelling. Individuals who use both sedative–hypnotics and alcohol pose a real
challenge for detoxification, which generally should be conducted in an inpatient
setting and over a prolonged period.
During detoxification, some patients decompensate into psychosis,
depression, or severe anxiety. In such cases, careful evaluation of the withdrawal
medication regimen is of paramount importance. Anxiety symptoms can cause
an overestimation of withdrawal severity on the Clinical Institute Withdrawal
Assessment-Alcohol, revised and therefore result in overuse of medication for
withdrawal. If the decompensation is the result of inadequate dosing with the
withdrawal medication, the appropriate response is to increase that medication.
If the dose of the withdrawal medication appears to be adequate, other
medications may need to be added. Before selecting the alternative, however, it
is important to consider the potential side effects of the additional medication
and the possibility of interaction with the withdrawal medication. If withdrawal
medications are adequate and appropriate but the patient continues to
decompensate, nonaddicting psychotropic medications (such as antipsychotics,
anticonvulsants, or antidepressants) may be indicated for the treatment of
psychoses, depression, or anxiety emerging during withdrawal. After
detoxification is completed, the patient’s need for medications should be
reassessed. A trial period with no medications may be indicated.
Adolescents
Monitoring the Future is an ongoing study of the behaviors, attitudes, and values
of American secondary school students, college students, and young adults. Each
year, a total of ~50 000 8th, 10th, and 12th grade students are surveyed (12th
graders since 1975, and 8th and 10th graders since 1991). Study results are used
to monitor trends in substance use among adolescents and young adults. Recent
results from the survey found that teenagers’ use of drugs, alcohol, and tobacco
declined significantly in 2016, at rates that are at their lowest since the 1990s;
however, marijuana use still remains high among 12th graders (29). The
percentage using any illicit drug other than marijuana has been declining
gradually since about 2001. Contributing to the ongoing high rates of marijuana
use is the perception that marijuana is not harmful and increasing social
acceptance stemming from the legalization of marijuana in an increasing number
of states. The psychotherapeutic medications (i.e., amphetamines, sedatives,
tranquilizers, or opioids other than heroin) now make up a larger part of the
overall US drug problem in adolescents than was true 10-15 years ago (29). The
reason for this is multifactorial and includes increased prescribing of these
medications for legitimate purposes, increased advertising directly to consumers,
and a decline in the use of illicit substances. It seems likely that young people
are less concerned about the dangers of using these prescription drugs outside of
a medical regimen. Alcohol remains the substance most widely used by today’s
teenagers, but it, too, trended downward in 2016, continuing a longer-term
decline. Adolescents in detoxification pose somewhat different clinical issues
than do adults. Patterns of use, negative consequences, context, and control of
use may all be unique in adolescents in comparison to adults. Physical
dependence is often not as severe in the adolescent compared with the adult, and
the adolescent patient’s response to detoxification usually is more rapid than that
of the adult (6,30,31). Inquiring about academic performance, school attendance,
and disciplinary problems can be particularly important to help the practitioner
ascertain the adolescent’s risk of a substance use disorder. Behavioral problems
may be more indirect, and the potential for suicide needs to be evaluated
carefully. Substance use disorder, particularly when comorbid with depression,
contributes to an increased rate of suicide in this age group. Adolescents who are
undergoing detoxification need a structured environment that is nurturing and
supportive. This is especially important because adolescents are notorious for
leaving treatment against medical advice. Also, adolescents should be housed
separately from adults. Decisions about involving the family in treatment should
be made on a case-by-case basis and should reflect an assessment of family
functioning. Note that federal regulations allow methadone detoxification of
adolescents, but state regulations vary. Both methadone and buprenorphine have
documented efficacy for opioid detoxification in the adolescent population;
however, similar to adults, maintenance therapy compared to detoxification
appears to lead to improved treatment retention and treatment outcomes (32).
Older Adults
Possible factors that may impact the treatment of intoxication and withdrawal in
older adults include the increased likelihood of medical comorbidities with
multiple prescribed medications and prescribing physicians, greater access to
prescription medications (which may be misused), and possible impaired
mobility from either social isolation or general medical conditions resulting in
difficulty accessing clinic- or office-based treatment. It is essential to conduct a
complete assessment and careful monitoring of the patient for comorbid
conditions, such as respiratory or cardiac disease or diabetes (33). Because the
aging patient may be taking a number of prescription and over-the-counter
medications, the possibility of interactions cannot be ignored. For these reasons,
detoxification in a medically monitored or medically managed setting often is
required. The cumulative effects of years of drinking may lead to more severe
withdrawal symptoms in elderly persons (34). The shorter-acting
benzodiazepines may be of more clinical utility in this population given their
lower risk of oversedation, but then careful attention must be given to symptoms
that may emerge as they are tapered. It may be necessary to reduce the doses of
detoxification medications because of older patients’ slowed metabolism or
coexisting medical disorders.
Persons in Criminal Justice Settings

Persons who are incarcerated or in detention in holding cells or elsewhere should
be assessed for physical dependence on alcohol or other drugs because untreated
withdrawal from alcohol and sedative–hypnotics can be life-threatening.
Prevalence of physical dependence in these settings is higher than in the general
population because an estimated 70% of people arrested for violent offenses test
positive for substances. According to data from the Arrestee Drug Abuse
Monitoring program in 2000, 64% of male arrestees tested positive for at least
one of five illicit drugs (cocaine, opioids, marijuana, methamphetamines, and
PCP), and 36% reported heavy drinking in the 30 days before arrest (35). It is
therefore critical that criminal justice and treatment staff be trained to detect
signs and symptoms of substance use disorder and to refer clients for appropriate
medical treatment in cases of acute intoxication or withdrawal (36).
Although heroin withdrawal is not life-threatening to a healthy individual, it
can be very difficult for the individual and should be treated appropriately.
Patients who have been on opioid agonist treatment before being incarcerated
should continue to receive their usual dose of medication. Opioid agonist
treatment should be discontinued as gradually as possible if the jurisdiction or
setting does not allow patients to receive these medications while incarcerated.
Individuals who are on methadone maintenance may experience severe
withdrawal symptoms if the medication is stopped abruptly. Indeed, methadone
abstinence symptoms may persist for weeks or months and include severe
vomiting and diarrhea, which can lead to complications. Pain may be severe and
intractable. Detoxification protocols need not be modified for incarcerated
persons, except to the extent that state laws restrict the use of methadone or
buprenorphine in criminal justice settings. In such cases, linkages with local
methadone detoxification programs are advised.
In caring for incarcerated patients, the physician needs to be aware that in
some settings, there is an underground market for psychoactive medications.
Patients may try to deceive caregivers about their physical dependence to obtain
drugs for sale to others. For this reason, prison medical staff need special
training in patient assessment and detoxification (37).
CONCLUSIONS
The recognition and treatment of intoxication and withdrawal states represent
important initial steps in the treatment of alcohol or other drug addiction. The
primary goal of managing intoxication and withdrawal states is the prevention of
morbidity and mortality. Whereas the treatment of intoxication often takes place
in a medical setting, the treatment of withdrawal can occur in either an inpatient
or an outpatient setting. Many variables must be taken into consideration in
providing optimum care to patients who are undergoing treatment of withdrawal
states. The ASAM Criteria can aid the clinician in matching patients to the
appropriate levels of care for ongoing treatment of their addiction.
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CHAPTER 51
Management of Alcohol Intoxication
and Withdrawal
Alan A. Wartenberg
CHAPTER OUTLINE
Alcohol Intoxication
Hangover
Alcohol Withdrawal
Management of Alcohol Withdrawal Syndromes
Common Treatment Issues
Conclusions
Management of alcohol intoxication and withdrawal is one of the clinical issues

most frequently encountered by specialists in addiction medicine. Effective
approaches, with a strong scientific basis, have been developed to reduce the
incidence of serious complications.
ALCOHOL INTOXICATION
Clinical Picture
As blood alcohol concentration (BAC) rises so too does the clinical effect on the
individual (Table 51-1) (1). Alcohol intoxication is defined by clinical
manifestations of impairment that occur after alcohol consumption. The
symptoms (significant behavioral or psychological changes due to central
nervous system [CNS] effects) are reversible, specific to alcohol, and there must
have been recent ingestion. At a BAC between 20 and 99 mg%, loss of muscular
coordination begins, and changes in mood, personality, and behavior occur.
While a level of 80 mg% is considered legal intoxication in the United States,
many people, particularly younger or medically/psychiatrically compromised
individuals, may have significant impairment below that level. In some
jurisdictions, individuals below the legal drinking age (21) are considered to be
under the influence with levels of 50 mg%, with a few localities having a “zero
tolerance,” where any detectable BAC indicates legal impairment.
TABLE 51-1 Clinical Effects of Alcohol

aLevels of 200-300 mg%, particularly when reached quickly (“chugging”), may result in coma, aspiration,
and death in nontolerant individuals, particularly adolescents and young adults. In addition, presence of
other depressant drugs, even in therapeutic doses (benzodiazepines, sedative-hypnotics, opioids), may
result in respiratory depression, coma, and death at lower levels of alcohol.
As the blood alcohol level rises to the range of 100-199 mg%, neurological
impairment occurs, accompanied by prolonged reaction time, ataxia,
incoordination, and mental impairment. At a BAC of 200-299 mg%, obvious
intoxication is present, except in those persons with marked tolerance. Nausea
and vomiting, as well as marked ataxia, may occur. In very young and/or naïve
drinkers, BACs of 300 mg% may be associated with coma and death, especially
when levels are reached quickly (eg, “chugging” drinks). The presence of other
sedating medications or substances may result in additive or synergistic effects,
increasing toxicity.
As the BAC rises to 300-399 mg%, hypothermia may occur, along with
severe dysarthria and amnesia, with stage I anesthesia. At BAC levels between
400 and 799 mg%, the onset of alcoholic coma occurs. The precise level at
which this occurs depends on tolerance; some persons experience coma at BACs
of 300 mg%, whereas others do not experience it until the BAC approaches 600
mg%, depending largely on tolerance as well as the rapidity of reaching the peak
BAC. Highly tolerant patients may be awake and conversant with levels that
produce obtundation and even coma in less tolerant individuals.
BACs between 600 and 800 mg% are commonly fatal. Progressive
obtundation develops, accompanied by decreases in respiration, blood pressure,
and body temperature. The patient may develop urinary incontinence or
retention, while reflexes are markedly decreased or absent. Death may occur
from the loss of airway-protective reflexes (with subsequent airway obstruction
by the flaccid tongue), from pulmonary aspiration of gastric contents, or from
respiratory arrest arising from profound CNS depression.
Management
The medical management of alcohol intoxication and overdose is supportive.
The primary goal of management of alcohol intoxication is to prevent harm to
the patient from severe respiratory depression and to protect the airway against
aspiration. Even with very high BACs, survival is probable if the respiratory and
cardiovascular systems can be supported. Attention must be paid to the potential
presence of nonbeverage alcohol (methyl alcohol, isopropyl alcohol, or ethylene
glycol) as well as coingestion of other toxins (eg, opioids, benzodiazepines,
tricyclic antidepressants) since these intoxications may present a similar clinical
picture but require different management.
Medical treatment is supportive in the alcohol-intoxicated patient. As with
all patients with impaired consciousness, intravenous glucose should be given if
rapid testing of blood glucose is not immediately available, after first giving
intravenous thiamine. These are of importance in alcohol intoxication as ethanol
can impair gluconeogenesis, with an increased risk of hypoglycemia, and alcohol
use disorder places the individual at an increased risk of thiamine deficiency.
Whenever feasible, intravenous thiamine (generally 100 mg or more) should be
given before glucose, particularly if glucose is given in large amounts or high
concentrations.
It also is important to assess whether the patient has ingested other drugs in
addition to alcohol, because these drugs may further suppress the CNS and alter
the approach to treatment. Alcohol is rapidly absorbed into the bloodstream, so
induction of emesis or gastric lavage is not indicated unless a substantial
ingestion has occurred within the preceding 30-60 minutes or when other drug
ingestion is suspected. Induced emesis may be useful at the scene (eg, with
children at home) if it can be given within a few minutes of exposure. However,
syrup of ipecac is no longer recommended, because of its toxicity if induction of
emesis is unsuccessful.
Mechanical induction of emesis (ie, stimulating the gag reflex with fingers
or instruments) has been discouraged because of the possibility of trauma to the
upper airway. Similarly, gastric lavage is indicated only if the patient presents in
the emergency department soon after ingestion. Activated charcoal does not
efficiently absorb ethanol but may be given if other toxins have been ingested.
More than 90% of alcohol is oxidized in the liver, and at the levels seen
clinically, the rate of oxidation follows zero order kinetics; alcohol metabolism is
independent of time and concentration of the drug. Elimination thus occurs at a
fixed rate, with the level falling at a rate of about 20 mg/dL/h in a nontolerant
individual; rates are higher in those with tolerance. In extreme cases of alcohol
intoxication, hemodialysis (or peritoneal dialysis) can be used because it
efficiently removes alcohol, but it is needed only rarely because supportive care
usually is sufficient. Hemoperfusion and forced diuresis are not effective.
The acutely intoxicated patient may exhibit some agitation as part of the
intoxication syndrome. This is best managed nonpharmacologically. Support and
reassurance are helpful in dealing with agitation in an acutely intoxicated patient.
On rare occasions, if pharmacological intervention is needed to manage a mildly
or moderately intoxicated individual’s behavior in a medical setting,
intramuscular administration of a rapid-onset, short-acting benzodiazepine, such
as lorazepam, alone or in combination with a neuroleptic agent such as
haloperidol, can be useful. Caution must be exercised with a potential synergistic
response between the alcohol already in the patient’s system and an exogenously
administered sedative–hypnotic, so this approach should be used only as a last
resort and not in individuals with high blood alcohol levels. If such an approach
is used, low doses (ie, haloperidol 1 mg with lorazepam 1 mg) are
recommended. Higher benzodiazepine doses may result in respiratory
depression, vomiting, and aspiration, as well as the potential for “paradoxical”
increased agitation by increasing intoxication.
There are no antidotes to alcohol that act like naloxone (an opioid
antagonist) or flumazenil (a benzodiazepine/GABA antagonist). Metadoxine has
been used to increase the metabolism of alcohol and shorten the period of
intoxication (2). It has been found to affect biochemical parameters and thus also
may be useful in amelioration of alcoholic hepatitis (3) with effects on early
survival; however, studies have not yet demonstrated improvements in long-term
clinical outcomes.
However, while a few trials with relatively few patients have shown a
reduction in time to release from emergency departments, there is no strong
evidence that metadoxine improves outcomes over conservative therapies, and
its routine use is not recommended in acute alcohol intoxication.
HANGOVER
Hangover is a constellation of unpleasant physical and mental symptoms that
occur after heavy alcohol intake. Headache, malaise, diarrhea, nausea, and
difficulty concentrating are the most common symptoms, often accompanied by
sensitivity to light or sound, sweating, and anxiety. About 75% of individuals
who drink to intoxication report experiencing a hangover at least some of the
time. The primary alcohol-related morbidity in “lower-risk” drinkers is
hangover. Because people who drink alcohol but do not exceed risky drinking
limits make up most of the workforce, the greatest cost incurred by alcohol in
the workplace is the decreased productivity caused by hangover-induced
absenteeism or poor job performance. In addition to the personal discomfort,
hangover increases the risk for injury and poor job performance. Patients with
hangover have diminished visuospatial skills and dexterity with impairment
demonstrated in pilots, automobile drivers, and skiers. There are also adverse
effects on managerial skills and tasks (4).
The pathophysiology of hangover is not completely understood. In part, it is
believed to be the effect of the intermediate product of ethanol metabolism,
acetaldehyde. In addition, congeners, by-products of individual alcohol
preparations found primarily in dark liquors such as brandy, whiskey, wine, and
tequila, appear to play a role because they increase the frequency and severity of
hangover. Clear liquors, such as rum, vodka, and gin, cause hangover less
frequently (4,5). Dehydration, electrolyte imbalance, disruption of sleep and
other biological rhythms, increased physical activity while intoxicated,
hypoglycemia, and the many hormonal disruptions caused by alcohol may also
play contributing roles (4,5). Patients with hangover have a diffuse slowing on
electroencephalography, which may persist up to 16 hours after blood alcohol
levels become undetectable (5).
Although many interventions have been tried to alleviate hangover
symptoms, to date, none has clearly demonstrated effectiveness in rigorous
investigations (5,6). Chinese publications, albeit with small samples, have found
encouraging results with flat lemon–lime soda as well as with red ginseng (7).
Conservative management offers the best course of treatment, and symptoms
generally resolve over 8-24 hours. Attentiveness to the quantity and quality of
alcohol consumed can have a significant effect on preventing hangover. Asking
patients about their hangover experiences offers an opportunity for education on
a common cause of physical, psychiatric, and occupational consequences of
drinking alcohol.
ALCOHOL WITHDRAWAL
Clinical Presentation
The relationship of heavy alcohol intake to certain syndromes has been
recognized since ancient times (Hippocrates, circa 400 BC). However, it was not
until the 18th century that the clinical manifestations of alcohol withdrawal were
clearly delineated. As is evident in the writings of Sutton, the vivid descriptions
of severe withdrawal written at that time remain relevant today:
It is preceded by tremors of the hands, restlessness, irregularity of thought,
deficiency of memory, anxiety to be company, dreadful nocturnal dreams when
the quantity of liquor through the day has been insufficient: much diminution of
appetite, especially an aversion to animal food; violent vomiting in the morning
and excessive perspiration from trivial causes. Confusion of thought arises to
such height that objects are seen of the most hideous forms, and in positions that
it is physically impossible they can be so situated; the patient generally sees flies
or other insects; or pieces of money which he anxiously desires to possess… (8).
For the most part, clinicians believed that these symptoms were a
consequence of alcohol itself. It was not until the second half of the 20th century
that their relationship to the cessation of chronic alcohol intake—a relationship
taken for granted today—was established. In 1953, Victor and Adams (9)
reported their careful observations of 286 consecutive patients with DSM-IV–
defined alcohol dependence admitted to an inner-city hospital, revealing the
consistent relationship of the cessation of alcohol to the emergence of clinical
symptoms. Their findings were supported in 1955 by a study of Isbell et al., (10)
in which 10 individuals with former opioid use disorder were given large
quantities of alcohol for 7-87 days and then withdrawn abruptly without
sedation. Over the next two decades, the concept of an alcohol withdrawal
syndrome was firmly established by further animal and human studies, and
diagnostic criteria based on empirical observation were developed. Today,
manifestations of alcohol withdrawal are generally categorized in clinical
practice as including the common alcohol withdrawal syndrome as well as the
more severe manifestations of hallucinations, seizures, and delirium.
Alcohol Withdrawal Syndrome

The current understanding of the alcohol withdrawal syndrome is reflected in the
diagnostic criteria of the Diagnostic and Statistical Manual of the American
Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders,
fourth and fifth editions (11,12). In those with physiological dependence on
alcohol, the clinical manifestations of alcohol withdrawal begin 6-24 hours after
the last drink (or after marked reduction in the quantity of alcohol consumed),
sometimes arising before the blood alcohol level has returned to zero. Early
withdrawal signs and symptoms include anxiety, sleep disturbances, vivid
dreams, anorexia, nausea, and headache. Physical signs include tachycardia,
elevation of blood pressure, hyperactive reflexes, sweating, and hyperthermia. A
tremor, best brought out by extension of the hands or tongue, may appear. This
tremor has a rate of six to eight cycles per second and appears on
electromyography to be an exaggeration of normal physiological tremor. The
severity of these symptoms varies greatly among individuals, but in a majority,
they are mild and transient, passing within 1-2 days (11,12).
Hallucinations
In mild alcohol withdrawal, patients may experience perceptual distortions of a
visual, auditory, and tactile nature. Lights may seem too bright or sounds too
loud and startling. A sensation of “pins and needles” may be experienced. In
more severe cases of withdrawal, these misperceptions may develop into frank
hallucinations. Visual hallucinations are most common and frequently involve
some type of animal life, such as seeing a dog or rodent in the room. Auditory
hallucinations may begin as unformed sounds (such as clicks or buzzing) and
progress to hearing voices. In contrast to the auditory hallucinations of
schizophrenia, which may be of religious or political significance, these voices
often are of friends or relatives and frequently are accusatory in nature. Tactile
hallucinations may involve a sensation of bugs or insects crawling on the skin,
known as formication. In milder cases of withdrawal, the patient’s sensorium is
otherwise clear, and the patient retains insight that the hallucinations are not real.
In more severe withdrawal, this insight may be lost. Hallucinosis can occur in
the absence of other withdrawal symptoms. They should be distinguished from
the hallucinosis that can be part of delirium tremens (DTs).
Alcohol Withdrawal Seizures

Grand mal seizures are another manifestation of alcohol withdrawal. Withdrawal
seizures occurred in 23% of the patients studied by Victor and Adams, in 33% of
the patients in Isbell’s study who drank the longest (for 48-87 days), and in 11%
of placebo-treated patients who were enrolled in prospective controlled studies
examining the effectiveness of benzodiazepines in symptomatic withdrawal (13-
16). Withdrawal seizures usually begin within 8-24 hours after the patient’s last
drink and may occur before the blood alcohol level has returned to zero. Most
are generalized major motor seizures, occurring singly or in a burst of several
seizures over a period of 1-6 hours. Although <3% of withdrawal seizures
evolve into status epilepticus, alcohol withdrawal has been found to be a
contributing cause in up to 15% of status epilepticus patients (17,18). Like
hallucinosis, seizures can sometimes occur with other symptoms of withdrawal
minimal or absent. This is particularly the case in patients who are taking low-
dose benzodiazepines, other sedatives, or adrenergic blocking agents, such as
beta-blockers or alpha-2-blockers, but also can be seen in elderly or debilitated
patients.
Seizures peak 24 hours after the last drink, corresponding to the peak of
withdrawal-induced electroencephalogram (EEG) abnormalities, which include
increased amplitude, a photomyoclonic response, and spontaneous paroxysmal
activity. These EEG abnormalities are transient, in keeping with the brevity of
the convulsive attacks. Except for this brief period after withdrawal, the
incidence of EEG abnormalities in patients with withdrawal seizures is not
greater than in the normal population (18). The risk of withdrawal seizures
appears to be in part genetically determined and is increased in patients with past
withdrawal seizures or in those who are undergoing concurrent withdrawal from
benzodiazepines or other sedative–hypnotic drugs. The misuse of
benzodiazepines increases the likelihood of status epilepticus when withdrawing
from both drugs.
There also is evidence that the risk of seizures increases as an individual
undergoes repeated withdrawals (19). This association has been described as a
“kindling effect,” which refers to animal studies demonstrating that repeated
subcortical electrical stimulation is associated with increases in seizure
susceptibility (20). Animal studies have supported this kindling hypothesis in
alcohol withdrawal, demonstrating that submitting animals to repeated alcohol
withdrawal episodes increases their risk of withdrawal seizures. There is
emerging evidence that this effect occurs in humans as well (21-24).
Alcohol Withdrawal Delirium

Withdrawal is highly individualized in both severity and duration. For up to 90%
of patients, withdrawal does not progress beyond the mild to moderate
symptoms described previously, peaking between 24 and 36 hours and gradually
subsiding. In other patients, however, manifestations can include delirium. The
diagnostic criteria are delineated in the DSM-5 (12). In the classic cases of
withdrawal delirium, the manifestations of withdrawal steadily worsen and
progress into a severe life-threatening delirium accompanied by an autonomic
storm: hence, the term delirium tremens (DTs). DTs generally appear 72-96
hours after the last drink. In their classic presentation, DTs are marked by all the
signs and symptoms of mild withdrawal but in a much more pronounced form,
with the development of marked tachycardia, tremor, diaphoresis, and fever. The
patient develops global confusion and disorientation to place and time, as well as
highly impaired attention (delirium). The patient may become absorbed in a
separate psychic reality, often believing him- or herself to be in a location other
than the hospital and misidentifies staff as personal acquaintances.
Hallucinations are frequent, and the patient usually has no insight into them.
Without insight, they can be extremely frightening to the patient, who may react
in a way that poses a threat to the patients’ or the staff’s safety.
Marked psychomotor activity may develop, with severe agitation in some
cases or continuous low-level motor activity in others, so that activities such as
efforts to get out of bed can last for hours. Severe disruption of the normal
sleep–wake cycle also is common and may be marked by the absence of clear
sleep for several days. The duration of the delirium is variable but averages 2-3
days in most studies (25). In some cases, the delirium is relatively brief, lasting
only a few hours before the patient regains orientation. In other cases, the patient
remains delirious for several days, with reports of periods lasting 50 days before
the confusion clears (26). Before the development of effective treatment,
mortality in DTs was substantial. With the development of effective therapy,
including intensive care, death from DTs is an unusual event (17,25).
Because the clinical syndrome of delirium has become more carefully and
broadly studied, and standard diagnostic criteria have been developed, it is
becoming apparent that many cases of delirium during alcohol withdrawal occur
without the autonomic storm associated with classically described DTs.
Although the terms “alcohol withdrawal delirium” and “DTs” are often used
interchangeably (9,10), many cases of delirium in alcohol withdrawal are mild
and transient. In one retrospective chart review of 284 patients undergoing
withdrawal, 20 patients were identified as meeting DSM-IV-TR criteria for
alcohol withdrawal delirium, while only 3 had the syndrome of DTs (27). This is
an area needing further investigation, including the role that treatment with
sedative–hypnotics or concurrent medical illness may play in the development of
mild delirium in alcohol withdrawal.
Alcohol Withdrawal Severity Scales

Because alcohol withdrawal involves a constellation of nonspecific findings,
efforts have been made to develop structured withdrawal severity assessment
scales to objectively quantify the severity of withdrawal. Several such scales
have been published in the literature (28-30). The most extensively studied and
best known is the Clinical Institute Withdrawal Assessment-Alcohol, or CIWA-
A, and a shortened version known as the CIWA-A Revised, or Clinical Institute
Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) (Table 51-2)
(29,30). The CIWA-Ar has well-documented reliability, reproducibility, and
validity based on comparisons with ratings of withdrawal severity by
experienced clinicians. The CIWA-Ar and similar scales require 2-5 minutes to
complete and have proved useful in a variety of settings, including withdrawal
management units, psychiatric units, medical/surgical wards, and intensive care
units. Such scales allow rapid documentation of the patient’s signs and
symptoms and provide a simple summary score that facilitates accurate and
objective communication among staff. In the case of the CIWA-Ar, a score ≤8
indicates mild withdrawal, a score of 11-15 moderate withdrawal, and a score
>15 severe withdrawal. Patients consistently scoring <8 rarely require intensive
monitoring, while those with scores of 11-15 need monitoring at least every 2-4
hours, while those with scores >15 may need a telemetry or intensive care
setting.
TABLE 51-2 Clinical Institute Withdrawal Assessment

of Alcohol Scale, Revised (CIWA-Ar)
This assessment for monitoring withdrawal symptoms requires approximately 5 minutes to administer. The
maximum score is 67 (see instrument). Patients scoring <10 do not usually need additional medication for
withdrawal.
From Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised Clinical
Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar). Br J Addict. 1989;84:1353-1357. Ref.
(29).
A careful analysis of symptoms, in an inpatient (ASAM level IV) withdrawal

management setting, recorded using withdrawal scales found that patients with
symptomatic withdrawal segregated into distinct clinical groups. Approximately
20% had no significant withdrawal symptoms (14). Another 20% had only
vegetative (physical) signs, such as tremor and sweating, but no psychological
symptoms. The largest group, 40%, had both vegetative and mild to moderate
psychological symptoms, primarily anxiety. The last group, about 20% of
patients, had both vegetative and severe psychological symptoms with
disorientation, delirium, or hallucinations. As indicated previously, relatively
few patients in alcohol withdrawal experience the adrenergic and clinical
manifestations of DTs. It is extremely important that staff responsible for patient
assessment be adequately trained in the utilization of the CIWA-Ar. One
common error is to assess the patient who is clinically intoxicated (or who has
other acute medical illness), which may result in a high score because of
nonspecific responses (nausea, headache, anxiety) and thus allow treatment of an
already intoxicated individual (or one with another medical cause of symptoms)
with benzodiazepines, with the potential for increased intoxication, respiratory
depression, vomiting and aspiration, and other complications. The reverse can
also be problematic, with inexperienced raters underscoring withdrawal
symptoms resulting in rapidly progressing withdrawal without the balance of
proper pharmacological treatment.
The responsible clinician (physician, nurse practitioner, physicians’ assistant
or doctor of pharmacy) should be thoroughly familiar with the instrument and
should train nurses and other health professionals who will be monitoring the
patients. Interobserver variability may occur and lead to inappropriate scoring
(high or low) when the observers have not had adequate training in
differentiating the differing anchor points given in the scoring instrument.
Professionals using the CIWA-Ar need to understand that it is not a diagnostic
instrument for alcohol withdrawal; the clinician must diagnose alcohol
withdrawal based on the clinical setting, including patient history and careful
examination (particularly a thorough neurological and mental status exam).
Confounding or exacerbating conditions, such as hypoglycemia, head trauma,
CNS infections, other drug influences, and metabolic disturbances, must be
appropriately excluded. Once the withdrawal syndrome is recognized, the
CIWA-Ar can assist in determining its severity and assist in establishing the
effects of treatment on its course. Clinicians utilizing such scales must
understand that there may also be confounding factors present, which may
increase the score (concomitant dehydration, infection, other causes of
hyperautonomic signs and symptoms) or may decrease it (advanced age, use of
beta-blockers or other sympatholytic drugs).
There have been several recent studies using more complex withdrawal
scales, which divide withdrawal into its autonomic, psychological, and
perceptual components and score them separately (31), with a proposal to treat
the autonomic component (if dominant) with adrenergic blocking agents (ie,
beta-blockers), the anxiety/psychological component with benzodiazepines, and
the perceptual disturbances with neuroleptic agents. Another withdrawal scale
simplifies the CIWA-Ar, using fewer parameters and simpler scoring—the
HAWP (Highland Alcohol Withdrawal Protocol)—with excellent results in a
retrospective study (32). An even simpler three-item scale, the AST (anxiety,
sweating, tremor) produced good results but in a study with only 85 patients
(33). Larger prospective studies, including head-to-head comparisons of the
performance of newer scales, including their performance in guiding treatment,
against the CIWA-Ar, are needed before their widespread acceptance by
clinicians.
Predictors of Severe Withdrawal

Withdrawal scales can also contribute to appropriate triage of patients as it has
been shown that high scores early in the course are predictive of the
development of seizures and delirium. Those with low scores on withdrawal
scales (10 or below on the CIWA-Ar) over the first 24-48 hours, particularly in
those with such scores who have taken no benzodiazepines, have consistently
been found to be at little or no risk for severe withdrawal. Other risk factors for
severe withdrawal include prior DTs or withdrawal seizures. The presence of
marked autonomic hyperactivity (commonly measured as elevated heart rate on
admission), elevated blood alcohol level of 100 mg/dL or higher at the time of
admission, and serum electrolyte abnormalities, and acute medical
comorbidities, particularly infection and trauma, are other clinical findings
associated with an increased rate of DTs or severe withdrawal. Characteristics
that have not been useful in triaging patients include the amount of daily intake,
duration of heavy drinking, age, and gender, though recent regular heavy intake
is a sine qua non for withdrawal risk, and longer duration of physical
dependence has predicted the incidence of symptomatic withdrawal. At least one
rating system has been developed combining multiple items to predict the
severity of withdrawal (31), but none are precise enough to be relied on
exclusively. This study identified patients at low risk for severe withdrawal with
high reliability. The clinical utility of this rating system has not been established
and likely requires further study.
Pathophysiology
Goldstein and Goldstein (34) proposed in 1961 that physical dependence
develops as a cell or organism makes homeostatic adjustments to compensate for
the primary effect of a drug. The primary effect of alcohol on the CNS is as a
depressant. With chronic exposure, there are compensatory adjustments to this
chronic depressant effect, with down-regulation of inhibitory systems and up-
regulation of excitatory systems. This represents a shift from homeostasis to
allostasis. With abrupt abstinence from alcohol, these relative deficiencies in
inhibitory influences and relative excesses in excitatory influences are suddenly
unmasked, leading to the appearance of withdrawal phenomena. The withdrawal
symptoms last until the body readjusts to the absence of the alcohol and
establishes a new equilibrium. Two neurotransmitter systems appear to play a
central role in the development of alcohol withdrawal syndrome. Alcohol exerts
its effects in part by directly or indirectly enhancing the effect of GABA, a major
inhibitory neurotransmitter. GABA mediates typical sedative–hypnotic effects
such as sedation, muscle relaxation, and a raised seizure threshold. Chronic
alcohol intake leads to an adaptive suppression of GABA activity. A sudden
relative deficiency in GABA neurotransmitter activity is produced with alcohol
abstinence and is believed to contribute to the anxiety, increased psychomotor
activity, and predisposition to seizures seen in withdrawal. Although alcohol
enhances the effect of GABA, it inhibits the sensitivity of the autonomic
adrenergic systems, with a resulting up-regulation with chronic alcohol intake.
The discontinuation of alcohol leads to rebound over activity of the brain and
peripheral noradrenergic systems. Increased sympathetic autonomic activity
contributes to such acute manifestations as tachycardia, hypertension, tremor,
diaphoresis, and anxiety (34,35).
A second neurotransmitter, norepinephrine, also seems to be important in
alcohol withdrawal presentations. Norepinephrine’s metabolites are elevated in
plasma, urine, and cerebral spinal fluid during withdrawal; levels of metabolites
correlate significantly with the sympathetic nervous system signs of withdrawal
(36). Research has identified other neural effects of chronic alcohol intake,
including effects on serotonergic systems, neuronal calcium channels, glutamate
receptors, cyclic AMP systems, and the hypothalamic–pituitary–adrenal
neuroendocrine axis, and these too may play a role in the pathophysiology of
withdrawal. Other recent studies suggest that the glutamatergic system and
NMDA (N-methyl-D-aspartate) dysregulation play a role in the development of
CNS excitation as well, particularly seizures and delirium (37).
Genetics
The role of genetics in alcohol withdrawal is a topic of active investigation. In
animal models, the development of selectively bred strains demonstrates that
severity of withdrawal and risk of seizures are strongly influenced by genotype.
Investigations in humans have focused on genes regulating neurotransmitter
systems. Several studies have found an association of the A9 allele, which
affects central dopamine functions, with severity of alcohol withdrawal, alcohol
withdrawal seizures, and DTs (38-40). To date, no relationship with genes
involved in the serotonin, GABAergic, or endorphinergic systems has been
found (41). Although these findings are not of immediate clinical use, genetic
studies may shed light on basic pathophysiology and, at some point, assist in
identifying high-risk individuals who may benefit from tailored therapy,
including those with genetic susceptibility to specific alcohol-related organ
damage, such as liver disease (42).
Role of Alcohol Withdrawal in Diagnostic

Classification
When DSM-III-R moved to a broad definition of alcohol dependence, it
removed any requirement for physiological components, tolerance and
withdrawal, for a diagnosis of alcohol dependence. This was done without
intensive study of what effect would occur if neither was required for a
diagnosis. DSM-IV did add a request to subtype dependence into groups with
and without physiological components. Intervening studies have shown that
~60% of individuals meeting DSM-IV criteria for alcohol dependence report
withdrawal symptoms, another 35% report tolerance without withdrawal
symptoms, and only 5% report neither. Of the seven DSM-IV dependence items,
withdrawal symptoms have been most strongly associated with an increased
number of alcohol-related problems, higher number of drinks per occasion, and
future difficulties (43). Alternative approaches to DSM-IV have been proposed
that reinstitute withdrawal as a required feature, with evidence that such
approaches offer better validity and better discrimination between the
dependence and abuse classifications (43,44).
The role of withdrawal in the diagnostic taxonomy of alcohol use disorders
continues to be investigated and debated. While the DSM-5 eliminates the
abuse/dependence dichotomy, and instead uses substance use disorder—alcohol
—based on the presence of 11 criteria (the same as the current criteria except
with recurrent legal difficulties being replaced by a craving criterion) (44), and
with severity indicators for absent (0 to 1 criterion), mild (2 to 3 criteria),
moderate (4 to 5 criteria), and severe (6 or greater criteria) (12), definitions and
criteria for alcohol withdrawal syndromes are not significantly different from
those in the DSM-IV-TR.
MANAGEMENT OF ALCOHOL
WITHDRAWAL SYNDROMES
General Principles
The primary goals of the treatment of alcohol withdrawal syndromes are to first
assure clinical stability of the patient and second encourage ongoing treatment
(eg, rehabilitation) of a patient’s alcohol use disorder. The first step in managing
the patient with alcohol withdrawal is to perform an assessment for the presence
of medical and psychiatric conditions. Chronic alcohol intake is associated with
the development of many acute and chronic medical problems. The clinician
needs to determine whether there are acute conditions that require hospital
treatment or chronic conditions that may alter the approach to the management
of withdrawal because they could be exacerbated significantly by the
development of withdrawal or its treatment. Pertinent laboratory tests generally
include complete blood count, electrolytes, magnesium, calcium, phosphate,
liver enzymes, urine drug screen, pregnancy test (when appropriate), and breath
or blood alcohol level. However, in patients at low risk for withdrawal requiring
pharmacological intervention, and who have no history of serious
medical/psychiatric problems, social setting detoxification without such
laboratory studies is feasible (vide infra -Social Setting Withdrawal
Management).
Others, depending on suspected co-occurring conditions, may include skin
test for tuberculosis, chest x-ray, electrocardiogram, and tests for viral hepatitis,
HIV, other infections, or sexually transmitted diseases. General management also
involves maintaining adequate fluid balance, correction of electrolyte
deficiencies, and attendance to the patient’s nutritional needs. Patients in early
withdrawal often are volume overloaded so that aggressive volume repletion
usually is not necessary unless there have been significant fluid losses from
vomiting or diarrhea. Volume status should be assessed by usual clinical signs
and symptoms, as well as by laboratory means when indicated. Supportive care
and reassurance from healthcare personnel are important elements of
comfortable withdrawal management and help to facilitate continuing treatment.
Supportive nonpharmacological care is an important and useful element in
the management of all patients undergoing withdrawal. Simple interventions
such as reassurance, reality orientation, monitoring of signs and symptoms of
withdrawal, and general nursing care are effective. There has been interest in the
possible value of complementary and alternative medicine for alcohol
withdrawal. Controlled trials of acupuncture have not demonstrated effectiveness
(45), whereas massage therapy did reduce alcohol withdrawal scores (46). It is
important to note that all these supportive measures do not prevent the
development of major complications such as seizures and are not adequate by
themselves to manage the patient with or at elevated risk for severe withdrawal
or delirium, in which case pharmacological intervention is required.
Pharmacological Management of
Uncomplicated Withdrawal Syndrome
The medical literature on the pharmacological management of alcohol
withdrawal has been comprehensively reviewed as part of the American Society
of Addiction Medicine (ASAM) evidence-based clinical practice guideline
efforts (17,25). This review of the evidence indicated that the cornerstone of
pharmacological management of withdrawal is the use of benzodiazepines, a
conclusion supported by more recent systematic reviews (47-50).
Benzodiazepines
Benzodiazepines are pharmacologically cross-tolerant with alcohol and have the
similar effect of enhancing the effect of GABA-induced sedation. A specific
benzodiazepine receptor site has been identified on the GABA receptor complex.
It is believed that the provision of benzodiazepines alleviates the acute
deficiency of GABA neurotransmitter activity that occurs with sudden cessation
of alcohol intake. Studies have consistently shown that benzodiazepines are
more effective than placebo in reducing the signs and symptoms of withdrawal.
Meta-analyses of prospective placebo-controlled trials of patients admitted
with symptomatic withdrawal have shown a highly significant reduction in
seizures, with a risk reduction of 7.7 seizures per 100 patients treated (17), as
well as in delirium, with a risk reduction of 4.9 cases of delirium per 100
patients treated (25). Trials comparing different benzodiazepines indicate that all
are similarly efficacious in reducing signs and symptoms of withdrawal.
However, longer-acting agents such as diazepam and chlordiazepoxide may be
more effective in preventing seizures. Longer-acting agents also may contribute
to an overall smoother withdrawal course, with a reduction in breakthrough or
rebound symptoms. On the other hand, pharmacological data and clinical
experience suggest that longer-acting agents can pose a risk of excess sedation in
some patients, including elderly persons and patients with significant liver
disease (hepatic synthetic dysfunction), and in patients with chronic pulmonary
disease, where prolonged respiratory depression may occur. In such patients,
shorter-acting agents such as lorazepam or oxazepam may be preferable; also,
these agents have the added advantage of avoiding phase I metabolism via the
cytochrome P-450 system—which may be advantageous in the setting of
impaired hepatic function.
Another consideration in the choice of benzodiazepine is the rapidity of
onset. Certain agents with rapid onset of action (such as diazepam, alprazolam,
and lorazepam) demonstrate greater potential for misuse or diversion than do
agents with a slower onset of action (such as chlordiazepoxide and oxazepam).
This consideration may be of relevance in an outpatient setting or for patients
with a past benzodiazepine misuse or disorder. However, when rapid control of
symptoms is needed, medications with faster onset offer an advantage, and in the
context of treating withdrawal, which particularly in the outpatient setting is of
short duration, the potential for misuse is rarely a clinical concern. A final
consideration in the choice of benzodiazepine is cost, as these agents vary
considerably in price. Given the evidence of equal efficacy, if a specific agent is
available to a practitioner or program at a lower cost, cost is a legitimate factor
to consider. The pharmacokinetics of different benzodiazepines should be taken
into consideration depending upon the clinical circumstances, including the age
and health of the patient, potential drug–drug interactions, and the stage and
severity of withdrawal. Younger, healthier patients generally tolerate longer-
acting drugs, which may produce a smoother course. Shorter-acting agents may
be better tolerated in older, sicker patients, particularly those with hepatic
insufficiency and/or pulmonary disease.
If patients are assessed for signs of oversedation prior to each dose, and
when at peak levels of receiving benzodiazepine, clinically serious oversedation
can be avoided, even if longer-acting agents are employed. Drug latency may
also be an issue when patients present with moderate to severe withdrawal, since
several commonly used drugs have longer periods between oral ingestion and
peak levels, such as oxazepam (which takes 1.5-2 hours to peak) or
chlordiazepoxide (1-2 hours), while diazepam may reach peak levels in 20-30
minutes. Since oxazepam is relatively short acting, the long latency and the rapid
excretion may produce a “choppy” course; in those with hepatic disease,
lorazepam may be an equally effective and safe option, with both more rapid
absorption and a longer period of clinical activity. Use of oxazepam with longer
dosing intervals (6-8 hours), particularly late in treatment, may result in an
increase in withdrawal manifestations, including seizures (51). There is no
reason to use more than one benzodiazepine; but in some cases adjunctive
medications may be helpful (vide infra).
Attention to tapering doses can be important when shorter-acting agents are
used as tolerance to them can develop rapidly and withdrawal from them can
lead to symptoms including seizures. While physical dependence upon
benzodiazepines given therapeutically is a legitimate concern, it rarely occurs
unless the benzodiazepine has been prescribed for 10-14 days, although the
author has rarely seen shorter courses leading to withdrawal (51).
Studies have indicated that nonbenzodiazepine sedative–hypnotics (eg,
barbiturates) also are effective in reducing the signs and symptoms of
withdrawal, but nonbenzodiazepine agents have not been as extensively studied,
and the size of studies of these drugs is not adequate to draw conclusions as to
their degree of effectiveness in reducing seizures and delirium, and they have a
less favorable toxic to therapeutic index. Benzodiazepines have a greater margin
of safety, with a lower risk of respiratory depression, as well as overall lower
misuse potential than the nonbenzodiazepine agents. Phenobarbital, a long-
acting barbiturate, still is used by some programs, as it has well-documented
anticonvulsant activity, is inexpensive, and has low misuse liability. However, as
with all barbiturates, oversedation is commonly associated with both depressed
consciousness and potential respiratory depression. It is critically important to
assess every patient for signs and symptoms of oversedation (sustained
nystagmus, dysarthria, dysmetria, ataxia, mood lability, and depressed level of
consciousness) prior to receiving additional doses and to withhold additional
doses if such signs or symptoms are present. Chlormethiazole, an agent with
benzodiazepine-like and anticonvulsant effects, while widely used elsewhere, is
unavailable in the United States.
Determining the Dosing Schedule

In many studies examining the effectiveness of various medications for
withdrawal, the medications were given in fixed amounts at scheduled times
(such as chlordiazepoxide 50 mg every 6 hours) and were given for periods of 5-
7 days. However, it has been shown that many patients can go through
withdrawal with only minor symptoms even though they receive little or no
medication (14,15). An alternative to giving medication on a fixed schedule is
known as symptom-triggered therapy. In this approach, the patient is monitored
through the use of a structured assessment scale and given medication only when
symptoms cross a threshold of severity. Well-designed studies have
demonstrated that this approach is as effective as fixed-dose therapy but leads to
the administration of significantly less medication and a significantly shorter
duration of treatment (15-17,50).
Symptom-triggered therapy also facilitates the delivery of large amounts of
medication quickly to patients who evidence rapidly escalating withdrawal and
thus reduces the risk of undertreatment that may arise with the use of fixed
doses. For programs specializing in the management of addiction, use of a
symptom-triggered approach with the utilization of a severity scale offers
significant advantages. However, there may be situations in which the provision
of fixed doses remains appropriate. For example, in patients admitted to general
medical or surgical wards, the nursing staff may not have the training or
experience to implement the regular use of scales to monitor patients. In certain
patients, such as those with severe coronary artery disease, the clinician may
wish to prevent the development of even minor symptoms of withdrawal.
Finally, because a history of past withdrawal seizures is a risk factor for seizures
during a withdrawal episode, and because withdrawal seizures usually occur
early in withdrawal, some practitioners administer fixed doses (or at least one
single dose regardless of symptoms) to patients with a history of withdrawal
seizures or who are otherwise at higher risk for symptomatic withdrawal such as
those with acute medical, surgical, or psychiatric illnesses. Whenever fixed
doses are given, it is very important that allowances be made to provide
additional medication if the fixed dose should prove inadequate to control
symptoms. In other words, despite the rationale for fixed dosing often being an
inability to monitor patients frequently as is required by symptom-triggered
therapy, fixed dosing does not obviate this need.
Loading dose therapy may also be considered, which involves monitoring
the patient with CIWA-Ar scores until they reach a predetermined set point
(generally 8-15) and then giving diazepam (10-20 mg), clorazepate (3.75-7.5
mg), or chlordiazepoxide (50-100 mg) on an hourly basis, evaluating the patient
prior to each dose until symptoms diminish or signs of oversedation develop—
sustained nystagmus, ataxia, dysarthria, mood lability, or oversedation itself
(somnolence not responsive to a normal-level voice) (49,50). The patient is then
monitored for 2-3 hours without further medication. The average patient
received three to five doses before reaching the end point, and 80% of patients
were adequately treated with a single episode of loading, while an additional
10% required a second loading dose regimen within the first 24 hours. One-tenth
of patients could not be successfully treated with this approach, presumably
because of up-regulation of P-450 hepatic cytochrome enzymes in these patients,
such that usual longer-acting benzodiazepines in effect were shorter acting in
these patients.
Treatment should allow for a degree of individualization so that patients can
receive large amounts of medication rapidly if needed. In all cases, medications
should be administered by a route that has been shown to have reliable
absorption. Therefore, the benzodiazepines should be administered orally or,
when necessary, intravenously. An exception is lorazepam, which has good
intramuscular and sublingual absorption. In the past, intramuscular
administration was commonly used. However, for most agents, intramuscular
absorption is extremely variable, leading to problems when rapid control of
symptoms is necessary and with delayed appearance of oversedation when large
amounts are administered. Examples of some treatment regimens consistent with
current recommendations are shown in Table 51-3.
TABLE 51-3 Examples of Specific Pharmacologic

Treatment Regimens
Adapted from Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and
evidence-based practice guideline. American Society of Addiction Medicine Working Group on
Pharmacological Management of Alcohol Withdrawal. JAMA. 1997;278:144-151; and Mayo-Smith MF,
Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium. An evidence-based practice
guideline. Arch Intern Med. 2004;164:1405-1412.
One technique is to use fixed-dose regimens that can be loosely based on the
potential for mild, moderate, or severe withdrawal and then to order as-needed
(prn) doses based on the development of an arbitrary CIWA-Ar score of 10-15. If
the CIWA-Ar fails to come down to below 10 after one to two additional doses,
the clinician should reassess the situation to determine that the medication is
being given at an appropriate dose by an appropriate route and that comorbid
issues are not present. If two as-needed doses fail to reduce the severity of
withdrawal, the entire regimen should be reconsidered, with higher standing
doses and/or consideration of absorption issues and switching to a parenteral
regimen. Similarly, hold orders should require not giving doses in patients who
are oversedated; if doses are withheld more than twice, the regimen should
similarly be reevaluated, with orders for lower standing doses. A major mistake
is to continue tapering standing doses in patients who are receiving frequent as-
needed doses. Another error is to give reduced doses to patients actively
manifesting toxicity when it is necessary to completely withhold doses of the
drug until no signs of toxicity are present. Tapering or stopping should not begin
until the patient is stable and CIWA-Ar scores are consistently below 10.
Anticonvulsants
Carbamazepine has been widely used in Europe for alcohol withdrawal and has
been shown to be equal in efficacy to benzodiazepines for patients with mild to
moderate withdrawal. Fixed, tapering doses of carbamazepine are without
significant toxicity when used in 5- to 7-day protocols for alcohol withdrawal
and are associated with less psychiatric distress, a faster return to work, less
rebound symptoms, and reduced posttreatment drinking (52). When compared
with placebo, there is significantly less use of benzodiazepines for breakthrough
symptoms. Carbamazepine does not potentiate the centrally mediated respiratory
depression caused by alcohol, does not inhibit learning (an important side effect
of larger doses of benzodiazepines), and has no addictive potential. It has well-
documented anticonvulsant activity and prevents alcohol withdrawal seizures in
animal studies. One problem, however, is that rapid dose escalation is not well
tolerated, and there are no trials showing seizure (and DTs) prevention during
withdrawal in humans.
Although the evidence base is smaller, use of tapering doses of sodium
valproate could be used in similar fashion. Both medications may also be used as
adjuncts to benzodiazepine-based regimens in patients who have past recurrent
withdrawal seizures, with prominent mood lability during withdrawal or with
concurrent benzodiazepine withdrawal. However, studies of adequate size to
assess the efficacy of these agents in preventing withdrawal seizures or delirium
are not yet available. Carbamazepine is only available in oral form, making it
difficult to titrate doses rapidly for the more symptomatic or rapidly worsening
patient. Valproate, however, is available in parenteral form, and oral loading
doses may be given. Patients treated with carbamazepine or sodium valproate
should be monitored using withdrawal scales and receive benzodiazepines if
severe withdrawal symptoms emerge. Both these agents have interactions with
other drugs and have hepatic and/or hematological toxicities and thus must be
used carefully, if at all, in patients with certain comorbid medical disorders.
While some authors are enthusiastic about anticonvulsants and recommend
them for not only mild to moderate but even severe withdrawal (52,53), the
authors of a Cochrane analysis felt that evidence was insufficient to recommend
their use (54). Furthermore, since they have not been shown to prevent the most
serious complications of alcohol withdrawal (seizures and DTs), they should not
be used as monotherapy without benzodiazepines in people at risk for such
complications.
The routine use of phenytoin had been advocated as a method to prevent the
occurrence of withdrawal seizures. However, methodologically sound trials have
shown that phenytoin is ineffective in preventing recurrent withdrawal seizures
(55,56). Moreover, studies have shown that appropriately used benzodiazepines
are extremely effective in preventing withdrawal seizures and that the addition of
phenytoin does not lead to improved outcomes. Its use has been largely
abandoned, particularly since many patients ended up taking it chronically, and it
became a common cause of phenytoin withdrawal seizures in people with
alcohol use disorder.
Anticonvulsants such as gabapentin and vigabatrin show promise for use in
alcohol withdrawal as they may have fewer side effects and be better tolerated.
One recent study reported success in using a combination of tiapride and
levetiracetam (57). Baclofen, a centrally GABA-active agent, has also been used
but has its own physical dependency liability. However, until multiple replicated
randomized clinical trials are reported with adequate numbers of patients, the use
of these agents should be considered investigational and, if used, should be
reserved for those with mild to moderate withdrawal in lower-risk patients who
could be treated without medications or who are treated only for mild symptom
control, particularly if they are being used as the sole treatment. In addition,
there is little data supporting efficacy of these agents in preventing or treating
alcohol withdrawal delirium or alcohol withdrawal seizures. A conservative
recommendation would be to use these agents as adjuncts in addition to
benzodiazepine therapy, rather than a replacement for them. However,
gabapentin has shown promise in both inpatient and outpatient settings for the
treatment of mild to moderate withdrawal symptoms in selected patients (58).
However, it should be used with great caution in people with addiction because
of its own addictive potential.
Other Agents
Beta-adrenergic–blocking agents, such as atenolol and propranolol, as well as
centrally acting alpha-adrenergic agonists, such as clonidine, also are effective in
ameliorating symptoms in patients with mild to moderate withdrawal, primarily
by reducing the autonomic nervous system manifestations of withdrawal.
However, these agents do not have known anticonvulsant activity, and the
studies to date have not been large enough to determine their effectiveness in
reducing seizures or delirium (24,28).
Beta-blockers pose a special problem in this regard because delirium is a
known, albeit rare, side effect of these drugs. In addition, there is concern that
selective reduction in certain manifestations of withdrawal may mask the
development of other significant withdrawal symptoms and make it difficult to
utilize withdrawal scales to guide treatment (15,16,25). The author has seen
many patients who were treated with beta-blockers manifest both seizures and
delirium as their first symptom of alcohol withdrawal. However, they may be
useful for controlling autonomic signs in people (eg, those with severe cardiac
risks) for whom they could pose a danger.
Neuroleptic agents, including the phenothiazines (eg, chlorpromazine,
prochlorperazine) and the butyrophenones (haloperidol and droperidol),
demonstrate some effectiveness in reducing the signs and symptoms of
withdrawal and for a time were used extensively for that purpose. However,
these agents are less effective than benzodiazepines in preventing delirium and
may lead to an increase in the rate of seizures. Neuroleptic agents are widely
used to calm agitated patients and are useful for this purpose in the setting of
alcohol withdrawal as well. They should not be used alone but always in
conjunction with a benzodiazepine; moreover, neuroleptic agents with less effect
on the seizure threshold, such as haloperidol, should be selected. There is limited
published experience with the use of second-generation (or “atypical”)
antipsychotics, such as olanzapine, aripiprazole, risperidone, and others,
although there is no clinical or pharmacological reason that they should not be
successful for this indication. In addition, several authors have published a series
of case reports of samples of hospitalized patients treated with
dexmedetomidine, a centrally acting alpha-2 agonist, used for the treatment of
alcohol withdrawal syndrome and specifically alcohol withdrawal delirium.
Several of these case reports indicate that the use of dexmedetomidine reduced
the need for benzodiazepines. The role of this medication in the management of
alcohol withdrawal remains to be clarified; at present, it should not be used as a
sole pharmaceutical treatment for alcohol withdrawal syndromes (vide infra,
Patients Admitted for Medical/Surgical Treatment), except in highly monitored
setting with experience in its use.
It has long been recognized that magnesium levels often are low during
alcohol withdrawal. A closer study has found that magnesium levels usually are
normal at admission but then drop later in withdrawal, before spontaneously
returning to normal as symptoms subside. Only one randomized trial of
magnesium during withdrawal has been performed, and that study found no
difference in severity of withdrawal or rate of seizures, even after adjustment for
magnesium levels. Providing supplemental oral magnesium to patients with a
documented low magnesium level is without significant risk, but routine
administration of magnesium, either oral or intramuscular, for withdrawal is no
longer recommended, except when hypomagnesemia and hypokalemia are both
present. In sicker and/or more debilitated patients, evaluation of phosphorus
stores, particularly after refeeding, should be considered, with repletion of those
with hypophosphatemia.
Ethanol
Case series describing oral or intravenous alcohol for the prevention or treatment
of withdrawal symptoms continue to be published in the surgical literature, but
no well-designed controlled trials evaluating the safety or relative efficacy of this
approach, compared either with placebo or to benzodiazepines, have been
performed (17,25). Despite the relative lack of evidence of oral and intravenous
alcohol for the management of alcohol withdrawal, several hospitals continue to
use intravenous or oral alcohol in the management of alcohol withdrawal (60-
63). Intravenous alcohol infusions require close monitoring because of the
potential toxicity of alcohol. Dosing for alcohol withdrawal is not clear. As a
pharmacological agent, ethyl alcohol has numerous adverse effects, including its
well-known hepatic, gastrointestinal, and neuropathic toxicities, as well as its
effects on mental status and judgment. Given the proven efficacy and safety of
other agents, the use of oral or intravenous alcohol for alcohol withdrawal
management is strongly discouraged—the ASAM practice guidelines
recommend against its use (17,25). However, the use of alcohol in the field to
taper a patient down while awaiting access to medical management, such as in
rural or military deployed settings where alcohol withdrawal medications are not
immediately available, may be considered in rare situations.
Thiamine and Other Vitamins

A final agent with an important role in the management of patients withdrawing
from alcohol is thiamine. Patients with alcohol use disorder are at risk for
thiamine deficiency, which may lead to Wernicke and/or Korsakoff syndromes.
Wernicke disease is an illness of acute onset characterized by the triad of mental
disturbance, paralysis of eye movements, and ataxia. The ocular abnormality
usually is weakness or paralysis of abduction (sixth nerve palsy), which
invariably is bilateral, although rarely symmetric. It is accompanied by diplopia,
strabismus, and nystagmus. The ataxia primarily affects gait and stance. Mental
status changes typically involve a global confusional and apathetic state, but in
some patients, a relatively disproportionate disorder of retentive memory is
apparent (Korsakoff syndrome). Wernicke-Korsakoff syndrome is a neurological
emergency that should be treated with the immediate parenteral administration
of thiamine, with long-term thiamine, and other B vitamin replacement
(9,17,25).
Dosage regimens vary widely, and there is little human experimental
evidence to support one regimen over another; a dose of 50 mg intravenously
and 50 mg intramuscularly is commonly recommended, as is 100 mg
intravenously once and/or 100 mg orally daily for 3 days. Delay in provision of
thiamine increases the risk of permanent memory damage. Sicker patients should
be considered for parenteral thiamine, while oral repletion is probably adequate
in healthier patients without apparent dietary deficiencies. In patients with
clinical evidence of thiamine deficiencies, such as memory issues, high-output
heart failure (beriberi), or neuropathy, thiamine and multivitamin
supplementation should be prolonged and, perhaps, indefinite.
The provision of intravenous glucose solutions may exhaust a patient’s
reserve of B vitamins, acutely precipitating Wernicke disease. Therefore,
intravenous glucose always should be accompanied by the administration of
thiamine in the patient with alcohol use disorder. Ocular palsies may respond
within hours, whereas the gait and cognitive problems of Wernicke-Korsakoff
syndrome improve more slowly. As the apathy, drowsiness, and confusion
recede, the patient may be left with a permanent defect in retentive memory and
learning known as Korsakoff psychosis (a misnomer, as there is typically no
psychosis, thus some have advocated a renaming to Korsakoff amnesia). To
reduce the risk of these sequelae, all patients presenting with alcohol withdrawal
should receive thiamine at the time of initial presentation, followed by oral
supplementation for several weeks. Since patients may also have other vitamin
deficiencies, supplementation with B complex vitamins, including folic acid, is
commonly employed. There are clinicians who believe that nutritional
deficiencies play a much larger role in the pathophysiology of alcohol use
disorder and alcohol withdrawal and who utilize amino acid precursors and other
supplements in treatment. However, there is a great deal of controversy over this
issue, and the data are inadequate to recommend use of such supplementation.
Management of the Patient After a
Withdrawal Seizure
The patient who presents after experiencing a withdrawal seizure raises several
management issues. It is important to recognize that not all seizures in patients
with alcohol use disorder are the result of withdrawal. In epidemiological
studies, the rate of epilepsy and seizures rises in parallel with the amount of an
individual’s alcohol intake. Patients with alcohol use disorder are at higher risk
for seizures unrelated to withdrawal. A careful history of the temporal
relationship of alcohol intake to the seizure should be obtained, and the
diagnosis of withdrawal seizure should be made only if there is a clear history of
a marked decrease or cessation of drinking in the 24-48 hours preceding the
seizure. All patients who present with their first seizure warrant a thorough
neurological examination and brain imaging, with lumbar puncture and EEG
also appropriate in some cases.
Patients who are known to have a past withdrawal seizures and who present
with a seizure that can be attributed clearly to withdrawal may not require a full
repeat evaluation. If the seizure was generalized and without focal elements, and
if a careful neurological examination reveals no evidence of focal deficits, there
is no suspicion of meningitis, and there is no history of recent major head
trauma; additional testing has an extremely low yield and may be safely omitted.
There is a 6- to 12-hour period during which there is an increased risk of seizure.
Withdrawal seizures often are multiple, with a second seizure occurring in one
case out of four. For the patient who presents with a withdrawal seizure, rapid
treatment is indicated to prevent further episodes. The parenteral administration
of a rapid-acting benzodiazepine such as diazepam or lorazepam is effective
(64).
Several studies have shown that phenytoin is no more effective than placebo
in preventing recurrent seizures (55,56). Initial treatment should be followed by
oral doses of longer-acting benzodiazepines over the ensuing 24-48 hours. Early
studies indicated that a withdrawal seizure places the patient at increased risk for
progression to DTs, so close monitoring is warranted. The period of postictal
“calm” or sedation may be followed, within 12-24 hours, by the development of
delirium, so that adequate ongoing monitoring and treatment are necessary.
Management of the Patient With Delirium

The patient who progresses to delirium raises many special management issues.
Older studies showed a mortality rate of up to 30% in DTs, but with modern
care, mortality has been reduced to <1% (15-17,48). The principles of successful
treatment involve adequate sedation and meticulous supportive medical care.
Such patients require close nursing observation and supportive care that
frequently necessitate admission to an intensive care unit. Careful management
of fluids and electrolytes is important, given the patient’s inability to manage his
own intake and the presence of marked autonomic hyperactivity. Delirium often
is encountered in patients admitted for acute medical problems whose alcohol
dependence was not recognized and whose withdrawal was not adequately
treated.
A high index of suspicion for the development of infection—whose
presenting signs may be masked by the fever, tachycardia, and confusion of the
underlying delirium—is essential, as is careful management of coexisting
medical conditions. The use of cross-tolerant sedative–hypnotics has been shown
to reduce mortality in DTs and is recommended (25,48). However, such
medications have not been shown to reverse the delirium or reduce its duration.
The goal is to sedate the patient to a point of light sleep or a calm but awake
state. This will control the patient’s agitation, preventing behavior posing a risk
to him- or herself as well as to staff, and allow staff to provide necessary
supportive medical care.
The use of intravenous benzodiazepines with rapid onset, such as diazepam,
has been shown to provide more rapid control of the patient’s symptoms. An
example of a widely used regimen is given in Table 51-3. The main complication
of therapy with diazepam is respiratory depression. Whenever this approach is
used, providers should have equipment and personnel immediately available to
provide respiratory support if needed. One advantage of diazepam is that its peak
onset occurs within 5 minutes of intravenous administration. This allows the
provider to deliver repeat boluses and titrate sedation quickly, with reduced
likelihood of a delayed appearance of oversedation.
However, intravenous diazepam has both an “alpha” and “beta” half-life.
The initial effect within 5 minutes is followed by a rapid uptake into lipid
storage sites; this may result in late oversedation if several repeated boluses are
used. Some clinicians prefer getting immediate control with intravenous
diazepam and then (after two or three bolus doses) switching to intravenous
lorazepam, which can maintain steady-state levels with bolus dosing without the
high lipophilicity resulting in fat redistribution. Alternatively, midazolam can be
used (1- to 2-mg boluses) to attain immediate control without a beta half-life
issue. The clinician should keep in mind that, secondary to the first-pass hepatic
metabolism of benzodiazepines, intravenous doses are equivalent to half the oral
dose.
Once established, delirium can be expected to last for hours, so diazepam
offers another advantage in that its longer half-life helps maintain sedation with
less chance of breakthrough agitation. Large doses of benzodiazepines may be
needed to control the agitation of patients in DTs, with hundreds and even
thousands of milligrams of diazepam or its equivalent used over the course of
treatment (26). The practitioner should not hesitate to use whatever amounts are
needed to control the agitation while keeping in mind the possible accumulation
of long-acting metabolites especially in patients with impaired hepatic function
or the elderly. In addition, intravenous preparations of both lorazepam and
diazepam are stabilized with propylene and polyethylene glycol, and repeated
high-dose use may result in both hyponatremia and metabolic acidosis. Careful
monitoring is required to prevent this complication. The use of continuous
infusions of benzodiazepines, particularly lorazepam and midazolam, has
become common in most critical care units. However, some evidence suggests
that this approach is no more effective than the use of bolus treatment and is
expensive. In the agitated patient, benzodiazepines can be supplemented with the
addition of neuroleptic agents such as haloperidol. As has been discussed, such
agents should not be used alone. Also, neuroleptic agents with less effect on
seizure threshold, such as haloperidol or droperidol, should be used. Newer
atypical antipsychotics are also effective.
For patients in whom withdrawal is not readily controlled with oral
benzodiazepines and who are beginning to demonstrate signs of agitation,
intramuscular administration of a combination of lorazepam and an
antipsychotic such as haloperidol often is effective in calming the patient, thus
avoiding the need to use intravenous administration. Some of the very high
doses used in treatment (thousands of milligrams of benzodiazepines) may in
some cases represent an iatrogenic complication of producing respiratory
depression requiring intubation, which then requires high-dose benzodiazepines
to prevent the patient extubating themselves. Recent popularity of use of
continuous infusions of the anesthetic propofol to maintain sedation has
increased this problem.
Use of high-dose intravenous benzodiazepines and propofol may lead to
increasing the dose again and a vicious cycle of medication-induced delirium
followed by further confusion upon lightening of the patient. In cases where the
patient has been delirious for more than 72 hours, careful consideration should
be given to this diagnosis. In such cases, since the patient is long past the peak
period of seizure risk, reduction of benzodiazepine dose should be strongly
considered, with the use of antipsychotic agents for continuing confusion or
agitation. Maintenance of a sleep-like state, with easy arousability by voice, is
preferable to production of deeper sedation; such deep sedation may require
intubation for airway protection or ventilation, which then requires even higher
doses of sedatives to prevent patients’ attempts to extubate themselves or “fight”
the ventilator. This may again lead to a positive feedback loop (vicious cycle) of
requiring deep sedation, followed by agitation and confusion upon lightening,
with reescalation of the dose and prolonged sedative treatment and extended
critical care unit stays.
Several recent papers from the critical care literature have indicated that
many patients requiring high-dose benzodiazepines do not need to be intubated
and that their clinical course is improved if they are carefully monitored with
oximetry and treated expectantly without intubation (65,66). In addition, use of
the alpha-2-blocker dexmedetomidine rather than benzodiazepine/propofol
infusions may allow successful treatment without intubation, with better clinical
outcomes and shorter critical care unit stays (67). Clinicians should follow this
literature closely for replication of these studies, which may alter our
consultation practices with these critically ill patients.
COMMON TREATMENT ISSUES
Location of Treatment Services

As both research and clinical experience demonstrated that pharmacological
therapy can significantly reduce the incidence of major complications associated
with alcohol withdrawal, it became common practice to admit patients to
inpatient units to provide 3-7 days of medication. However, such intensive—and
expensive—therapy is not necessary for many patients and increasing interest
has been shown in managing withdrawal on an outpatient basis. All patients
presenting for management of medically significant withdrawal should undergo
a comprehensive history and medical evaluation. Consideration should be given
to routine laboratory evaluation, particularly a complete blood count,
electrolytes, BUN/creatinine, and liver function tests. In some more debilitated
patients, evaluation of phosphorus and magnesium is appropriate. Other studies
should be done as clinically indicated.
For patients with only mild withdrawal symptoms, no past seizures or DTs,
and no concurrent significant medical or psychiatric conditions, management on
an outpatient basis is reasonable (68). Such patients should have a responsible
individual to monitor them and should be seen on a regular (daily if possible)
basis until they have been stabilized. Ready access, including transportation, to
emergency medical services should be available. In addition, many programs are
concentrating on sharply reducing the length of stay for patients undergoing
withdrawal. Patients may be treated in an observation unit or admitted for a 1-
day stay. If significant withdrawal symptoms do not develop, and the withdrawal
is easily controlled with little or no medication, patients can be discharged or
transferred to an intensive outpatient rehabilitation program. It should be noted
that such programs achieve success rates comparable to inpatient/residential
treatment for most patients (68,69). Patients who experience severe withdrawal
symptoms, however, need continuous close monitoring and nursing support.
Loading dose treatment, as described above, is particularly suited to outpatient
management (49). The ASAM patient placement criteria describe specific
characteristics for patients appropriate for ambulatory withdrawal management
(70).
Patients Admitted for Medical/Surgical

Treatment
Studies have shown that about 20% of patients admitted to the hospital have an
alcohol use disorder, and the rate among those admitted for acute trauma or for
conditions related to high alcohol intake, such as head and neck cancers, is even
higher. Thus, hospital admission is a frequent precipitating event for alcohol
withdrawal. Screening for unhealthy alcohol use and withdrawal risk if
excessive drinking is present should be universal at the time of hospital
admission but is not yet common practice. Patients thus may develop withdrawal
that goes unrecognized or becomes far advanced before being recognized and
treated. Withdrawal has been shown to contribute to higher postoperative
complications, mortality, and length of stay (71).
Unfortunately, it is all too common to proceed with elective surgery despite
knowledge of a current alcohol use disorder. Such patients should be screened
for unhealthy alcohol use and undergo medically managed withdrawal before
proceeding with surgery. Current management strategies for alcohol withdrawal
rely on quantitative assessment of withdrawal severity and were developed in
patients presenting specifically for alcohol withdrawal. However, signs and
symptoms of withdrawal are very nonspecific, and thus, they can be difficult to
differentiate from manifestations of acute medical conditions. Furthermore,
critically ill patients, who may have impaired consciousness or be on ventilators,
cannot provide much of the information required to assess severity of
withdrawal.
Nevertheless, use of alcohol withdrawal scales in general medical/surgical
patients has been studied and found to be valuable in selected patients (72). Low
withdrawal scales can be interpreted with confidence as indicating the absence
of significant withdrawal, although patients on beta-blockers and other
sympatholytic drugs may have falsely low scores. However, high scores have
many causes and must be interpreted with caution. Given the frequency of
alcohol use disorder in hospitalized patients, instituting standard screening,
assessment, and management protocols is appropriate. Patients requiring more
than small amounts of medication for withdrawal symptoms need individualized
assessment by clinicians experienced in the management of withdrawal.
Alcohol Withdrawal in U.S. Jails

Another event that frequently precipitates alcohol withdrawal is arrest and
incarceration. In 1997, surveys showed that of the 11 million individuals
arrested, ~1.2 million had alcohol dependence. Unfortunately, at the same time,
only 28% of jail administrators reported that their institutions ever provided
medically managed withdrawal for arrestees, despite the ruling of the U.S.
Supreme Court that failure to provide proper medical care amounts to a violation
of the Eighth Amendment of the U.S. Constitution proscribing cruel and unusual
punishment. Overall, in 1997, 750 000 arrestees were at risk for untreated
alcohol withdrawal (73). Because this situation has not changed significantly in
the intervening years, it is not surprising that inadequately treated alcohol (and
other drug) withdrawal has been shown to contribute to deaths among newly
arrested individuals. ASAM has issued a public policy statement on appropriate
withdrawal management services for individuals incarcerated in prisons and
jails, which recommends that incarcerated individuals should receive appropriate
screening and medical care to manage withdrawal syndromes (74).
The high-risk status of this population should be kept in mind as healthcare
professionals encounter patients referred from jails with possible withdrawal
symptoms. In addition, because of the potential for polysubstance use,
benzodiazepine or other sedative–hypnotic and opioid withdrawal may also be
present. Lastly, adequate provision of rehabilitative care in our prison system
must be a priority since many or most of these individuals commit their crimes
either under the influence of these drugs or to obtain money for their drugs. One
“silver lining” of the current opioid use disorder epidemic has been an increasing
recognition on the part of correctional system administrators and government
officials and regulators that provision of alcohol and drug treatment services in
the correctional system is inadequate and needs urgent remedy.
“Social Setting” Withdrawal Management

In some communities, nonmedical and nonpharmacological treatment has been
made available, often associated with free-standing withdrawal management
settings (so-called “public” withdrawal management programs) that offer drug-
free withdrawal for patients presenting with low likelihood for moderate to
severe withdrawal. In one report, these patients were monitored with the CIWA-
Ar technique on a regular basis, with increased monitoring for those who scored
>10. Patients who progressed to CIWA-Ar score >15 were referred to a local
hospital emergency department. In this setting, thousands of patients were safely
treated without medication, and a very small number of patients required referral
to a higher level of care. This was dependent, however, on good low-risk patient
selection and well-trained staff administering the CIWA-Ar (75). A review found
that many such programs, when well-run, can be both clinically efficacious and
cost-effective but that quality and services were highly variable (76).
CONCLUSIONS
It is important to remember that successful management of alcohol withdrawal is
only the first—and sometimes the most easily achieved—step toward the
primary goal of treating the patient’s underlying addiction to alcohol. The
underlying goals of the management of alcohol intoxication and withdrawal are
to assure the stability and safety of the patient and encourage ongoing treatment
of their alcohol misuse. It is important for the clinician to understand the risk
factors for alcohol withdrawal as well as its pathophysiology and course. In
addition, an understanding of the pharmacological principles of treatment
(including assessment of those whose withdrawal is likely to respond to
nonpharmacological measures, such as human contact and support) is more
important than memorization of protocols. Clinicians must have a good
understanding of both the pharmacodynamics and pharmacokinetics of treatment
agents, so that rational choices can be made in specific patients.
While no approach has been shown to be superior to others in the treatment
of unselected patients in alcohol withdrawal, certain regimens may have
advantages in specific populations in certain treatment settings. Physicians
treating large numbers of patients with alcohol use disorder should be
particularly knowledgeable about matching these treatments with their patients’
characteristics. Treatment decisions should be made using clinical algorithms,
which consider patients’ responses to treatment, with midcourse corrections
being made on the patients’ responses (or atypical or lack of response) to that
treatment. An excellent resource is the SAMHSA Treatment Improvement
Protocol (TIPs) series, which include an excellent and comprehensive review of
substance use disorder and withdrawal management (77). Updates of the TIP
series can be found online (78).
It has become increasingly common for patients to present with substance
use disorders involving multiple substances, and it is not uncommon for patients
to deny or minimize their use of benzodiazepines, other sedative–hypnotics, and
opioids (particularly if that use is illicit). Clinicians should carefully probe for
such history, utilizing information from collaterals as well as drug screening
tests, and be prepared to treat the other potential withdrawal syndromes.
Development of a plan to engage the patient in further treatment is a critical
component of withdrawal treatment and must not be overlooked. Failure to do
this increases the chance of revolving-door admissions for withdrawal
management, without assisting the patient’s entry into rehabilitation and
recovery. Use of motivational interviewing techniques may enhance clinicians’
ability to address the patient’s readiness to change and facilitate entry into
treatment (79). Specific motivational techniques adapted for alcohol and other
drug use disorders are available (80). Also, engagement of family is critical and
may be essential for the patient’s recovery, as well as assisting the family itself
(81,82).
Lastly, treatment of alcohol intoxication and withdrawal is only the first step
in assisting individuals with alcohol use disorder into recovery. Psychosocial
approaches are widely used in the United States and include twelve-step
facilitation and twelve-step programs, cognitive behavioral therapies,
motivational interviewing, and contingency management. The effectiveness of
these approaches can be significantly enhanced in many patients by specific
pharmacotherapies that reduce both craving for and the use of alcohol (83).
These medications are vastly underutilized. I urge my colleagues to consider the
use of these helpful agents in all their patients and to prescribe them when
appropriate (see Chapter 47).
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CHAPTER 52
Management of Sedative–Hypnotic
Intoxication and Withdrawal
Steven J. Eickelberg, William E. Dickinson, and Reham
A. Attia
CHAPTER OUTLINE
Introduction
Sedative–Hypnotic Intoxication and Overdose
Sedative–Hypnotic Withdrawal
Patient Evaluation and Management
Common Treatment Issues
Summary
INTRODUCTION
Sedative–hypnotics are a group of drugs that include benzodiazepines,
barbiturates, “Z-drugs,” and carbamates. They are widely used to decrease
anxiety, produce drowsiness facilitating sleep, and are among the most
extensively prescribed medications in the United States. Barbiturates were first
discovered by von Baeyer in 1864 (1). They were widely used until
benzodiazepines were introduced in the 1960s as a safer alternative;
benzodiazepines were preferred due to their lower potential for respiratory
depression and higher therapeutic index. However, the increase in
benzodiazepine use came with an increase in their misuse. According to the 2011
data from the Drug Abuse Warning Network (DAWN), sedative–hypnotic–
anxiolytics were the second most frequently reported drug class to cause an
emergency department visit (34%), surpassed only by opioids. Visits due to
benzodiazepines accounted for 29%. Visits to the emergency department related
to alprazolam alone increased by 166% over the 7-year period from 2004 to
2011. These findings are echoed in the 1987 recommendations of the Royal
College of Psychiatrists in Great Britain who recommended benzodiazepine
prescribing be curtailed to “no more than one month” citing that “consequences
of long-term usage are liable to outweigh the symptomatic relief” of anxiety
disorders (2).
Sedative–hypnotics are GABAergic agents that activate the GABAA receptor
system; the main inhibitory system in the brain. They use many of the same
biochemical and neurological pathways that alcohol uses; therefore, they have
similar dependence and withdrawal characteristics, and they exhibit cross-
tolerance. These substances work by stimulating the inhibitory neurotransmitters
in the gamma-aminobutyric acid (GABA) receptors (3). Although all sedatives
and hypnotics have mild stimulant properties at low doses, their primary effect is
to inhibit central nervous system (CNS) function. Medications in this class that
are commonly associated with severe withdrawal states include methaqualone,
phenobarbital, and benzodiazepines such as diazepam, lorazepam, alprazolam,
and clonazepam. Sedative medications associated with less severe clinical
withdrawal states include meprobamate and chlordiazepoxide.
SEDATIVE–HYPNOTIC INTOXICATION
AND OVERDOSE
Clinical Picture
Patients taking a low (therapeutic) dose of benzodiazepines experience impaired
motor activity and immediate memory as well as inability to retain new learned
material. These patients are also five times more likely to be in a motor vehicle
crash than their counterparts (4). The signs and symptoms of sedative–hypnotic
intoxication and overdose are similar for the various medications in the class
(Table 52-1). The patient with mild to moderate toxicity presents with slurred
speech, ataxia, and incoordination similar to that seen with alcohol intoxication
(5,6). On occasion, particularly in older adults, a paradoxical agitated confusion
and delirium may be produced. At more severe stages of intoxication, stupor,
and coma develop (5). Older nonbenzodiazepine agents (eg, glutethimide
[Doriden], barbiturates [Seconal, Nembutal], ethchlorvynol [Placidyl],
methaqualone [Quaalude], meprobamate [Miltown], chloral hydrate [Notec])
directly act on GABAA receptors regardless of the presence of GABA. Their
toxicity is progressive and ultimately leads to respiratory arrest or cardiovascular
collapse. Overdose with these older agents may also be associated with a variety
of agent-specific clinical manifestations, such as bullous skin lesions with
barbiturates (“barb blisters”), details of which can be found in resources on
toxicological emergencies (7).
TABLE 52-1 Diagnosis of Sedative–Hypnotic Overdose

An additional problem with several of the older nonbenzodiazepine sedative–
hypnotic medications is that, with regular use, tolerance to therapeutic effects
may develop but not to the lethal effects such as respiratory suppression.
Barbiturates are well known for having a narrow therapeutic index (small
difference between therapeutic and toxic dose that may lead to dose and blood
concentration and incur serious life-threatening adverse drug reactions). This
means that toxicity and overdose can occur with only small increases over the
individual’s regular intake. In overdose, barbiturates and older sedative–
hypnotics cause respiratory suppression, coma, and death.
This is not the case when benzodiazepines are used alone. A lethal dose has
not been established for any of the benzodiazepines, and there are very few well-
documented cases of death from ingestion of benzodiazepines alone. However,
combinations of high doses of benzodiazepines in combination with alcohol,
barbiturates, and/or opioids are particularly dangerous and may lead to severe
adverse consequences such as coma or death. Importantly, especially in light of
the current US opioid epidemic and high rates of opioid and benzodiazepine use,
benzodiazepine use in combination with opioids potentiates overdose possibility
(8). The few documented benzodiazepine-associated deaths have involved short-
acting, high-potency benzodiazepines such as alprazolam and triazolam (9),
administration of benzodiazepines by intravenous route, use by patients with
severe respiratory compromise, and when taken in combination with another
CNS depressant. Alprazolam and triazolam are triazolobenzodiazepines that
have higher affinities for central and peripheral benzodiazepine receptors than
other benzodiazepines. Also, triazolam use with cimetidine or erythromycin can
double its half-life and plasma levels, thus increasing its risk of toxicity (4).
Inappropriate intramuscular use of chlordiazepoxide can lead to erratic
absorption, producing respiratory compromise. Benzodiazepines are free of toxic
effects on peripheral (non-CNS) organ systems in either long-term use or acute
overdose.
Sedative–hypnotic–anxiolytics (including benzodiazepines) continue to be a
major cause of overdose when used with other substances because of their
synergistic effect with other agents such as alcohol, opioids, antihistamines, and
antipsychotics, anticonvulsants, tricyclic antidepressants, and other CNS
depressants. This is because the combination of these drug classes can be
sedating, suppress respiratory efforts, impair thought, slow response time, and
increase falls. It was recently reported that nearly 30% of fatal opioid overdoses
in the United States involve benzodiazepines. One study proposes that
eliminating concurrent use of benzodiazepines and opioids could reduce
overdose risk by 15% (10). The DAWN report of December 2014 showed that
38% of emergency room visits involving benzodiazepines combined with
opioids or alcohol resulted in more serious outcomes, especially in older
patients. This is of particular concern in light of recent findings showing an
increase in the number of concurrent benzodiazepine and opioid prescriptions
over the past decade (11).
Management
Evaluation begins with rapid assessment of the patient’s airway, breathing, and
circulation (ABCs of Basic Life Support). In severe cases, secure the
compromised airway with an endotracheal tube (ETT) and start oxygen therapy
with capnography, obtain intravenous access, and place on continuous cardiac
monitoring. Such patients who have been exposed to another CNS depressant
and require mechanical ventilation should be admitted to a critical care unit.
Gastrointestinal decontamination with activated charcoal is not advised because
of the increased risk of aspiration.
Alkalization of the urine may be helpful in eliminating phenobarbital, but
forced diuresis has not been shown to be helpful for any drugs in the class. In
extreme cases, hemoperfusion may have a role. Measurement of serum levels
can be helpful in documenting the identity and amounts of agents ingested, as
well as in tracking levels over time. However, immediate clinical management is
based on the patient’s condition rather than serum levels.
Flumazenil is a competitive benzodiazepine receptor antagonist with very
weak agonist properties at the benzodiazepine receptor (12). It can reverse the
sedative effects of benzodiazepines and may have a similar effect on ethanol,
barbiturates, and some general anesthetics. It has found a role in reversing the
effects of short-acting benzodiazepines, such as midazolam, after medical
procedures and may be used when benzodiazepines have been ingested alone as
an overdose. In such settings, slow intravenous titration in amounts not
exceeding 1 mg is recommended, with monitoring for the recurrence of sedation.
The effects of flumazenil are short-lived, and symptoms may return in 30-60
minutes. Moreover, its use has been associated with seizures and cardiac
arrhythmias. These adverse effects are more likely to occur when it is
administered rapidly in large amounts and in patients who have ingested a
sedative–hypnotic in combination with a substance capable of causing seizures,
such as a tricyclic antidepressant (13). Persons who are physiologically
dependent on benzodiazepines are at high risk of seizures when they are given
flumazenil. Flumazenil thus has not found a role as part of the standard “coma
cocktail” (containing thiamine, glucose, and naloxone) because it produces a
rapid benzodiazepine withdrawal. Its use in mixed overdoses or in patients who
have used benzodiazepines chronically is limited because of the risk of adverse
effects.
SEDATIVE–HYPNOTIC WITHDRAWAL
Overview
The use of most sedative, hypnotic, or anxiolytic agents can result in the
development of psychological dependence, physical dependence, or addiction. In
this chapter, “dependence” is used to refer to the host’s neurophysiological
adaptation to regular or chronic sedative–hypnotic use (physical dependence).
The definition of dependence includes adaptation to substance use that leads to
an abstinence syndrome with the abrupt and, at times, tapered cessation of use.
Withdrawal is tantamount to, and is defined by, the signs and symptoms
contained within the abstinence syndrome. This syndrome can occur with both
high- and low-dose use—even use at therapeutic levels monitored by a
physician. The development of dependence to sedative–hypnotic compounds is
similar across the classes of the benzodiazepines, the barbiturates, and the
nonbarbiturate/nonbenzodiazepine agents.
While withdrawal syndromes of all sedative–hypnotics and alcohol are
similar, differences in withdrawal syndrome characteristics and severity reflect
differences in the rate at which dependence is induced and the rapidity with
which symptoms occur upon discontinuation of the drug.
A clinically significant withdrawal syndrome is most likely to occur after
discontinuation of daily therapeutic dose (low-dose) use of a sedative–hypnotic
for at least 4-6 months or, at doses that exceed two to three times the upper limit
of recommended therapeutic use (high dose), for more than 2-3 months.
However, any withdrawal symptoms can occur sooner, as physical dependence
occurs. The time course and severity of the sedative–hypnotic withdrawal
syndrome reflect the influences of three pharmacological factors: (a) dose, (b)
duration of use, and (c) duration of medication action (Fig. 52-1), where the
duration of medication action is directly related to the elimination half-life at
steady-state conditions. Withdrawal severity has been related to dose and
duration of treatment. Latency to onset of withdrawal is related to the
elimination half-life (14).
Figure 52-1 Time course of sedative–hypnotic withdrawal.

Time course and potential withdrawal intensity as influenced
by dose and duration of drug action. HD, high dose; LD, low
or therapeutic dose; SA, short acting; LA, long acting; PW,
prolonged withdrawal.
Clinical research with benzodiazepines has identified additional medication and

host factors that influence the onset and severity of the withdrawal syndrome;
these factors are elaborated on in the following sections.
Signs and Symptoms of Discontinuation

The spectrum of signs and symptoms that are experienced most often during the
course of withdrawal are summarized in Table 52-2. Considerable variation
exists among patients in terms of the signs and symptoms of the abstinence
syndrome. Although Figure 52-1 appears to indicate that withdrawal follows a
smooth and predictable course, most patients experience significant moment-to-
moment quantitative and qualitative variations in their signs and symptoms.
Petursson (15) and Salzman (16) reviewed the frequency of various symptoms of
benzodiazepine withdrawal. Anxiety, insomnia, restlessness, agitation,
irritability, and muscle tension were very frequent. Less frequent were nausea,
diaphoresis, lethargy, aches and pains, coryza, hyperacusis, blurred vision,
nightmares, depression, hyperreflexia, and ataxia. Psychosis, seizures, confusion,
paranoid delusions, hallucinations, and persistent tinnitus were uncommon. The
areas under the curves in Figure 52-1 outline the potential time course and
withdrawal severity characteristics. The multitude of signs and symptoms
outlined in Table 52-2 illustrates that, in the absence of the knowledge that a
patient is withdrawing from a sedative–hypnotic, a number of medical or
psychiatric differential diagnoses would be entertained to explain the patient’s
condition.
TABLE 52-2 Clinical Manifestations of Sedative–

Hypnotic Withdrawal
Benzodiazepines
Benzodiazepine use, dependence, and withdrawal are much more thoroughly
researched than other classes of sedative–hypnotic compounds. Soon after
chlordiazepoxide (Librium, 1954) and diazepam (Valium, 1963) became
available commercially, clinical reports were published documenting a high-dose
discontinuation withdrawal syndrome with severe characteristics (seizures,
depression, delirium, psychosis) (17,18). Reports of a withdrawal syndrome after
discontinuation of long-term use of benzodiazepines at therapeutic doses were
published within the following decade (19,20). It now is well established that
benzodiazepine dependence, withdrawal, and difficulties in discontinuing
chronic benzodiazepine use are influenced by multiple pharmacological and host
factors (as discussed below).
Barbiturates
Reports in the medical literature evidenced an emerging awareness of barbiturate
dependence and an abstinence syndrome as early as the 1940s. The first
American article (21) directly addressing the barbiturate withdrawal syndrome
was followed by a clinical study that chronicled the signs and symptoms of the
barbiturate abstinence syndrome (22). Further studies quantified, with high-dose
use, the duration of barbiturate ingestion necessary for the appearance of mild,
moderate, and severe withdrawal symptoms (23,24). The first evidence that an
abstinence syndrome could occur after long-term therapeutic (low-dose)
barbiturate use was published nearly two decades later (25,26).
Treatment of barbiturate withdrawal with barbiturate substitution was
reported as early as 1953 (24). In 1970 and 1971, Smith and Wesson reported on
a protocol that employs phenobarbital substitution, stabilization, and tapering to
treat barbiturate dependence. Their technique is discussed later under “Sedative–
Hypnotic Tolerance Testing.”
Nonbarbiturate/Nonbenzodiazepine Agents
Z-drugs (zolpidem, zopiclone, and eszopiclone) were first hailed as a safer
alternative to benzodiazepines to treat insomnia until increasing reports of
complex sleep-related behaviors and falls in the elderly led to increased caution
and regulation of their use. They achieve their hypnotic effects through
preferential binding to the α1 subunit of the GABAA receptors. They reduce
sleep latency and improve sleep quality but do not significantly increase sleep
duration.
Because, like benzodiazepines, they work by increasing GABA transmission
at GABAA receptors, they have similar potential for misuse and a withdrawal
syndrome that seen from benzodiazepines (27). Of greatest concern is the
multitude of reports documenting severe withdrawal syndromes, marked by
delirium, psychosis, hallucinations, hyperthermia, cardiac arrests, and death
(28–35). Intoxication and overdose with Z-drugs present mainly as sedation and
coma and are managed by supportive measures. They rarely lead to death unless
they occur with polydrug use (27).
Benzodiazepine Discontinuation
The signs and symptoms experienced after the discontinuation of
benzodiazepine use have been described as falling into four categories: (a)
symptom recurrence or relapse, (b) rebound, (c) pseudowithdrawal, and (d) true
withdrawal.
Symptom recurrence or relapse is characterized by the recurrence of
symptoms (such as insomnia or anxiety) for which the benzodiazepine initially
was taken. The symptoms may be similar in character to the condition that
existed before treatment with medication. Relapse may occur after
discontinuation, with or without the prior existence of benzodiazepine
dependence. Reemergence of symptoms is quite common, exceeding 60%-80%
for anxiety and insomnia disorders (36,37). Symptom recurrence can present
rapidly or slowly over days to months after medication discontinuation.
This pattern can have important implications for routine reassessment of the
need for continued benzodiazepine use. The need for the benzodiazepine should
be reevaluated, with particular attention given to dose and duration. Because of
the concern of toxicity, when the need is diminished or eliminated, so should be
the benzodiazepine.
Rebound is marked by the development of symptoms, within hours to days
of medication discontinuation, which are qualitatively similar to the disorder for
which the benzodiazepine initially was prescribed. However, the symptoms are
transiently more intense than they were before drug treatment. Insomnia and
anxiety disorders are the best-studied examples (38). Rebound symptoms are of
short duration and are self-limited (37), which distinguishes this syndrome from
recurrence. Benzodiazepine tolerance is likely due to a pharmacodynamic
neuroadaptive phenomenon where GABA production is down-regulated, further
exacerbating underlying psychiatric issues.
Pseudowithdrawal and overinterpretation of symptoms may occur when
expectations of withdrawal lead to the experiencing of abstinence symptoms.
This effect has been observed in study patients who discontinued placebo
medication or continued benzodiazepine use but believed that the
benzodiazepine had been discontinued (39). In addition, expectations of
symptoms often are negatively influenced by concerns registered in the media or
by friends or physicians.
True withdrawal is marked by the emergence of psychological and somatic
signs and symptoms after the discontinuation of benzodiazepines in an
individual who is physically dependent on the medication. The withdrawal
syndrome can be suppressed by the reinstitution of the discontinued
benzodiazepine or another cross-tolerant sedative–hypnotic. Withdrawal from
benzodiazepines results from a reversal of the neuroadaptive changes in the CNS
that were induced by chronic benzodiazepine use. Withdrawal reflects a relative
temporal and temporary diminution of CNS GABAergic neuronal inhibition
coupled with an increased glutamate response to balance the benzodiazepine-
induced GABA release.
There is considerable individual variation over time among patients who
discontinue benzodiazepines. The benzodiazepine withdrawal syndrome
includes any of the spectrum of signs and symptoms listed in Table 52-2. Any
combination of signs and symptoms may be experienced with varying severity
throughout the initial 1-4 weeks of abstinence. None of the signs or symptoms of
the abstinence syndrome are pathognomonic of benzodiazepine withdrawal.
Many signs and symptoms are identical to those of anxiety or depressive
disorder. Common symptoms include tremor, muscle twitching, nausea and
vomiting, impaired concentration, restlessness, anxiety, anorexia, blurred vision,
irritability, insomnia, sweating, and weakness. Common clinical signs include
tachycardia, hypertension, hyperreflexia, mydriasis, and diaphoresis.
Neuropsychiatric symptoms—including perceptual distortions and
hypersensitivity to light, sound, and touch—are common. Many believe these
“sensory–perceptual symptoms” are most indicative of neurophysiological
withdrawal, but they rarely occur in the absence of some of the aforementioned
adrenergic or anxiety symptoms. Lack of clinical signs should not be considered
tantamount to the absence of a withdrawal syndrome.
The clinical withdrawal picture can consist primarily of subjective
symptoms, accompanied by few or no concurrently observable hyperadrenergic
signs or vital sign fluctuations as often occurs with acute alcohol withdrawal. It
is therefore not surprising that the CIWA-Ar scale that is used to evaluate
alcohol withdrawal is also used to assess benzodiazepine withdrawal.
These discontinuation syndromes often occur in combination. For example,
considerable overlap exists between the symptoms of recurrence in anxiety and
insomnia disorders and the signs and symptoms of rebound and withdrawal.
Clinical techniques that treat, minimize, and attenuate benzodiazepine abstinence
symptoms also effectively alleviate rebound. As a result, attention to sorting out
rebound from withdrawal is unnecessary (if not impossible). However, symptom
recurrence or relapse is common. Clinicians must be attuned to the emergence or
persistence of clinically important symptoms of relapse during and after the
period of acute withdrawal.
Prolonged Withdrawal/Post-Acute Withdrawal Syndrome

Some physicians report (40–42), and clinical experience confirms, that a small
proportion of patients, after long-term benzodiazepine use, experience a
prolonged syndrome of withdrawal. The signs and symptoms may persist for
weeks to months after discontinuation. The syndrome is notable for its irregular
and unpredictable day-to-day course and qualitative and quantitative differences
in symptoms from both the prebenzodiazepine use state and the acute
withdrawal period. It does not follow a linear pattern. Patients with prolonged
withdrawal often experience slowly abating—albeit characteristic waxing and
waning—symptoms of insomnia, perceptual disturbances, tremor, sensory
hypersensitivities, and anxiety. These symptoms can be discouraging to patients
early in recovery and are a great contributor to their relapse.
Role of the GABA–Benzodiazepine Receptor Complex

GABA is quantitatively the most important inhibitory neurotransmitter in the
CNS (43). It controls the state of excitability in all brain areas. GABAergic
neurons are widely distributed in the CNS, with 20%-25% of all central synapses
using GABAA receptors.
GABAA receptors are made up of five protein subunits surrounding a central
pore permeable to chloride ions (Fig. 52-2). Activating GABAA receptors opens
chloride channels causing chloride influx that hyperpolarizes neurons and
decreases excitability. GABAA receptors have different subtypes (isoforms)
depending upon the type of protein subunits present. Different isoforms have
different functions and respond to drugs differently. Receptors with two β plus a
γ2 or γ3 plus two α1, α2, or α3 subunits bind to benzodiazepines. Receptors with
α4, α6, γ1, and δ subunits are benzodiazepine insensitive, binding to GABA,
alcohol, and some general anesthetics but not to benzodiazepines. While
barbiturates and anesthetic steroids directly open chloride channels,
benzodiazepines modulate the capacity of GABA and therefore need GABA to
work (3,43) (Fig. 52-3). Neuronal inhibition results from neuronal membrane
hyperpolarization secondary to the flow of chloride ions down the
electrochemical gradient into the neuron (3).
Figure 52-2 The most important and most prevalent GABAA

—benzodiazepine receptor in the brain is made up from α1,
β2, and γ2 subunits, encoded by the same cluster of genes on
chromosome 5. The composition of the receptor subunits,
particularly α and γ subunits, seems to determine the
benzodiazepine pharmacology of the receptor, with different
subtypes having different sensitivities to benzodiazepine
receptor ligands. (From Higgitt A, Fonagy P. Benzodiazepine
dependence syndromes and syndromes of withdrawal. In:
Hallstrom C, ed. Benzodiazepine Dependence. New York,
NY: Oxford University Press, 1983:58-70.)
Figure 52-3 Schematic representation of the binding sites on

the GABAA—benzodiazepine receptor complex. Note that
agonists binding to the benzodiazepine receptor site do not
open the chloride channel directly, but rather augment the
capacity of GABA to do so. (This is a schematic diagram and
does not correspond directly to the protein subunits seen in
Figure 52-2.) (From Smith DE, Wesson DR. Benzodiazepine
dependency syndromes. J Psychoactive Drugs. 1983;15:85-
95.)
A series of studies by Miller et al. (44–47) illustrated that in a mouse model,

behavioral tolerance and discontinuation syndromes are temporally associated
with molecular/receptor level adaptations. The investigators reported that, as
tolerance to the ataxia-inducing effects of lorazepam developed behaviorally,
benzodiazepine and GABA receptors were down-regulated (through decreased
receptor number, decreased GABA receptor function, and diminished protein
synthesis for GABA receptors). After lorazepam was administered for 4 weeks,
it was abruptly discontinued. Concurrent with signs of withdrawal, GABA
receptors were up-regulated, and GABA receptor complex function was
enhanced (as evidenced by greater affinity for GABA, increased affinity of the
benzodiazepine receptor for benzodiazepines, increased benzodiazepine receptor
number).
The rate of onset of behavioral tolerance to alprazolam and clonazepam
followed by an abstinence syndrome after abrupt discontinuation was similarly
computed and then compared with that of lorazepam in a subsequent report (47).
Tolerance and withdrawal developed more rapidly with alprazolam (4 days for
tolerance; 2 days for withdrawal) than with lorazepam and clonazepam, which
were similar (7 days for tolerance; 4 days for withdrawal) (44,45,47). However,
there is no scientific evidence that there is a difference in physical dependence
potential among different benzodiazepines. These studies also demonstrated that
tolerance is primarily a pharmacodynamic, neuroadaptive phenomenon (brain
and plasma levels remained constant throughout the period of chronic
administration).
Dr. Christian Lüscher and colleagues at the University of Geneva,
Switzerland, have discovered that benzodiazepines act on the GABAA receptors
in the ventral tegmental area to release a surge of dopamine. Dopamine surges
have been linked to addiction (48). The initial change with abrupt withdrawal of
a benzodiazepine is the diminished activity of the GABAA–benzodiazepine
receptor complex. This is paired with an excitatory system heightened by the
chronic use of the benzodiazepine.
The amino acid L-glutamate is the major excitatory neurotransmitter in the
CNS. Glutamate receptors have been classified into two groups: the N-methyl-D-
aspartate (NMDA) receptors and non-NMDA receptors AMPA (alpha-amino-3-
hydoxy-5-methyl-4-isoxazole propionic acid) and kainate. Neuronal plasticity
between excitation and inhibition is a balance of GABAergic inhibition and
glutamatergic excitation (Fig. 52-4).
Figure 52-4 Effects of GABA and glutamate on the brain.
With chronic benzodiazepine use, changes occur at the cause a new level of
homeostasis. GABAA receptor expression changes with substitution of one
subunits subtype for another, changing the function of the receptor and
manifesting as tolerance to benzodiazepines. GABA receptors are down-
regulated to maintain baseline CNS inhibitory tone without causing
oversedation. By contrast glutamate-gated NMDA receptors are up-regulated. If
the sedative–hypnotic is rapidly decreased or stopped, there is a great imbalance
as the down-regulated GABA receptors are unable to overtake the up-regulated
glutamate receptors, resulting in withdrawal manifesting as CNS excitation. This
up-regulation of the CNS excitatory tone may be permanent. This may explain
why successive withdrawals can progressively increase intensity, known as the
kindling effect.
Pharmacological Characteristics Affecting
Withdrawal
Pharmacological factors (pharmacokinetics, dose, duration, and potency) are
primarily responsible for the relationship between various benzodiazepines and
the differing clinical manifestations of benzodiazepine withdrawal syndrome.
Pharmacokinetics
Benzodiazepine pharmacokinetics determine the onset of discontinuation
symptoms following chronic use. Cessation of use is followed by declining
blood levels of drug at receptor sites, brain, blood, and peripheral tissues, with
the rate of decline determined primarily by the elimination half-life. The onset,
duration, and severity of the withdrawal syndrome correlate with declining
serum levels of drug (17,44–46,49,50).
Withdrawal from short-acting benzodiazepines (such as lorazepam,
oxazepam, triazolam, alprazolam, and temazepam) occurs within 24 hours of
cessation (51) and peaks in severity within 1-5 days (51,52). Withdrawal from
long-acting benzodiazepines (such as diazepam, chlordiazepoxide, and
clonazepam) occurs within 5 days of cessation (36,51) and peaks at 1-9 days
(52).
Duration of acute withdrawal, from onset to the resolution of symptoms, can
be 7-21 days for short-acting and 10-28 days for long-acting benzodiazepines.
Abrupt discontinuation of short-acting benzodiazepines leads to rapid onset of a
withdrawal syndrome that is more intense than that experienced with long-acting
benzodiazepines (49,51,52).
Dose and Duration of Use

Higher doses and longer use place patients at greater risk for increased
withdrawal severity. Daily benzodiazepine use for 10 days or less can lead to
transient insomnia with medication cessation. Withdrawal syndrome following
short-term (<2-3 months) low-dose therapeutic use is mild (with symptoms such
as insomnia), and symptoms are easily managed. Vorma et al. (53) found that
people with lower benzodiazepine doses and no previous withdrawal attempts
were more successful with discontinuation. Withdrawal syndrome following
long-term (>1 year) therapeutic (low-dose) use can present with moderate to
severe symptoms (anywhere from 1 in 5 to all patients, depending most likely on
dose and duration and unknown patient factors) (51,52). Discontinuation of
high-dose (more than four or five times the high end of the therapeutic range for
longer than 6-12 weeks) benzodiazepine use leads to moderate withdrawal in all
patients and severe withdrawal signs and symptoms in most patients (54).
Use beyond 1 year may predispose patients to prolonged withdrawal
sequelae but is a less important factor in the severity of acute withdrawal (55).
Potency
Tolerance to the sedative and hypnotic effects develops most rapidly to shorter-
acting, higher-potency benzodiazepines (such as triazolam and alprazolam).
Withdrawal from these agents may be more intense and require more aggressive
attention and longer periods of medical monitoring than is the case with other
benzodiazepines (56,57).
Host Factors Affecting Withdrawal

In addition to the aforementioned pharmacological influences, host factors are
implicated in patients’ susceptibility to dependence and in the difficulty they
encounter in discontinuing benzodiazepines after they become dependent.
Clinically important patient factors include the following: psychiatric and
medical comorbidity, use of other substances, family history of alcohol use
disorder, age, sex, bariatric surgery, and pregnancy.
The primary clinical indication for benzodiazepine use involves treatment of the
highly prevalent conditions of insomnia, anxiety, thought, and mood disorders. It
follows that patients with chronic psychiatric disorders who are maintained on
benzodiazepines for more than 3-6 months will, in addition to their psychiatric
condition (adequately treated or not), also be physically dependent on the
benzodiazepine. Numerous benzodiazepine discontinuation studies (including
case–control, cohort, and retrospective studies) highlight the high (40%-100%)
prevalence of active concurrent psychiatric disorders seen at intake of
benzodiazepine discontinuation study participants (51,52,55,57,58). Most of
these studies demonstrate a correlation between the patient’s degree of
psychopathology and his or her withdrawal symptom severity and difficulty in
discontinuing use.
Rickels et al. (51) reported on 119 patients discontinuing long-term,
therapeutic dose use. They noted a 90% prevalence of initial, active
psychopathology with diagnoses that included generalized anxiety disorder
(44%), panic disorder (27%), depression (14%), and others (7%). Patients with
greater psychopathology required more support and assurance. The intensity of
the withdrawal syndrome was seen as partially a function of the degree of
psychopathology and other premorbid personality variables.
Rickels et al. (55) also studied abrupt and tapered discontinuation of long-
term, therapeutic dose benzodiazepine use. They found that 79%-84% of patients
had symptoms of anxiety and/or depression at intake (primary psychiatric
diagnoses included generalized anxiety disorder, panic disorder, and major
depression). They reported significantly greater withdrawal severity in patients
diagnosed with more initial psychopathology, dependent personality disorder, or
neuroticism. Patients with panic disorder were more vulnerable to withdrawal
than patients with generalized anxiety disorder (59).
Increased withdrawal symptoms also have been associated with high initial
anxiety or depression and decreased educational level (60). Clinicians
conducting benzodiazepine discontinuation thus must obtain psychiatric histories
while remaining vigilantly watchful for, and prepared to manage, the emergence
or reemergence of psychiatric disorders. Clinicians also must be aware that
patients with psychiatric symptoms or disorders often experience more severe
withdrawal symptoms and have greater difficulty discontinuing use. The
reduction of fear and anxiety symptoms during withdrawal was the best
predictor of a patient’s success for achieving and maintaining abstinence (61).
Concurrent Use of Other Substances

Concurrent regular use of other dependence-producing substances increases the
complexity of the benzodiazepine abstinence syndrome and the clinical situation
as a whole. Additional sedative–hypnotic, alcohol, opioid, and/or stimulant use
contributes to a withdrawal syndrome of increased severity and a less predictable
course. Opioid substance withdrawal contributes an additional cluster of signs
and symptoms where the anxiety, agitation, irritability, hyperarousal, and
adrenergic components of opioid and benzodiazepine withdrawal are additive,
often overlap, and lead to an exacerbation of overall symptoms. Psychomotor
stimulant withdrawal symptoms contribute factors from the opposite end of the
withdrawal spectrum (eg, apathy, hypersomnia, and lethargy). When stimulant
withdrawal is combined with sedative–hypnotic withdrawal, the clinical picture
can be quite variable, with hypersomnolence and lethargy mixed with symptoms
of severe agitation, depression, irritability, and somatosensory hypersensitivity.
Initial hypersomnolence and lethargy can mask symptoms of benzodiazepine
withdrawal, particularly involving benzodiazepines with a longer half-life.
Several factors underscore the need for clinicians to be aware of the high co-
occurrence of alcohol use disorders, anxiety disorders, or benzodiazepine
dependence and their potential influence on the benzodiazepine withdrawal
syndrome:
A high percentage of people who meet criteria for alcohol dependence

(DSM-III and DSM-III-R) use benzodiazepines regularly, ranging from
29% (62) to 33% (63) to 76% (64).
The rate of comorbid alcohol use disorders and anxiety disorders is reported
to be 18%-19% (65).
Patients dependent on alcohol have a high propensity for dependence on
benzodiazepines (64,66).
Exceeding one standard drink per day is a more significant predictor of

benzodiazepine withdrawal severity than dose or half-life of the medication (55).
Patients with high-dose benzodiazepine use who present for inpatient addiction
treatment exhibit a high rate (70%-96%) of concurrent substance dependence
(DSM-III and DSM-III-R) (57,63). DuPont (67) reported that >20% of patients
newly admitted to inpatient addiction treatment reported using benzodiazepines
at least weekly, 73% of people using heroin reported greater than weekly use,
and >15% of those using heroin used benzodiazepines daily (68).
It is uncommon for a patient with drug addiction to use a benzodiazepine as
an initial or primary drug (69). Instead, benzodiazepines are used in combination
with other psychoactive drugs. In addition, a high rate of benzodiazepine use in
methadone maintenance clinics is supported by numerous clinical surveys.
Consequently, clinicians must be aware of, and suspect, benzodiazepine use
in patients with any substance use disorders. Conversely, in persons using high-
dose benzodiazepine, other substance use must be assumed until ruled out.
Family History of Alcohol Use Disorder

Mood changes associated with lability or benzodiazepine misuse (and increased
propensity to develop dependence) have been reported after controlled clinical
administration of diazepam and alprazolam in adult sons of patients with severe
alcohol dependence (DSM-III-R) (64,70,71). Similar findings with alprazolam
have been reported in adult daughters of patients with alcohol dependence
(DSM-III-R) (72). This predisposition to misuse benzodiazepines is important,
because at least one study implicates a linkage of paternal history of alcohol use
disorder with increased withdrawal severity in patients discontinuing alprazolam
use (56).
Concurrent Medical Conditions

Benzodiazepine withdrawal should be avoided during acute medical or surgical
conditions because the physiological stress of withdrawal can adversely and
unnecessarily affect the course of the medical condition. On the other hand,
continued benzodiazepine use rarely has a negative effect on acute medical
conditions. In an acute medical situation, the goal of therapy for a patient
dependent on benzodiazepines is to provide adequate stabilization of the
benzodiazepine dose so as to prevent withdrawal.
Clinicians need to be secure in their understanding of the indications for
discontinuing long-term benzodiazepine use in patients with chronic medical,
including mental health, conditions. This understanding is particularly critical
when evaluating the discontinuation of benzodiazepines in patients with
conditions that are significantly influenced by adrenergic and psychological
stress factors (such as cardiac arrhythmia, asthma, systemic lupus erythematosus,
and inflammatory bowel disease). The risks of exacerbating the medical
condition through acute withdrawal or a protracted withdrawal course may
outweigh the longer-term benefits of benzodiazepine discontinuation.
Patients with chronic medical conditions may experience benzodiazepine
withdrawal more severely than others. Clinicians and patients must be aware
that, during withdrawal, difficulties in managing the medical condition (diabetes,
cardiovascular disease, thyroid disease, and arthritis) may emerge. The rate of
discontinuation is an important factor. Slower rates can improve the success of
withdrawal management. Achieving lower doses of benzodiazepine use is an
acceptable intermediate (and, in some patients, final) goal. It is important to
stabilize both the patient’s physical and psychological health at reduced
benzodiazepine levels before proceeding with further reductions.
Age
Anxiolytic use peaks between the ages of 50 and 65, whereas hypnotic use is
most frequent in the oldest age range (14). Because hepatic microsomal enzyme
oxidase system efficiency decreases with age, elderly patients may have
elimination half-lives that are two to five times slower than their younger
counterparts for most benzodiazepines (excepting lorazepam, temazepam, and
oxazepam). The withdrawal syndrome for elderly persons who are discontinuing
oxidatively metabolized benzodiazepines may be quite prolonged or approach
the severity of high-dose withdrawal secondary to the pharmacokinetic factors of
aging. The withdrawal course can become especially pernicious after
discontinuation of long-acting benzodiazepines that are metabolized to sedative–
hypnotic compounds with longer elimination half-lives (such as diazepam,
chlordiazepoxide, and flurazepam). In general, younger age is associated with
favorable withdrawal outcomes (73).
Sex
Worldwide, women are prescribed benzodiazepines twice as often as men;
hence, twice as many women as men are likely to become dependent (74).
Possibly compounding this trend are reports that female sex is a significant
predictor of increased withdrawal severity in patients undergoing tapered
cessation of long-term, therapeutic benzodiazepine use (55). However, sex has
not been implicated as an influential factor in abrupt cessation of long-term,
therapeutic dose use (52).
Bariatric Surgery
Studies show reduced serum levels of phenobarbital after Roux-en-Y gastric
bypass surgery. This is significant when using phenobarbital in medically
assisted withdrawal as will be later discussed. Such patients will require higher
doses of phenobarbital than anticipated (75).
Pregnancy
While medically assisted opioid withdrawal is contraindicated in pregnancy,
sedative–hypnotic–anxiolytic withdrawal can be accomplished however only
with caution and regular monitoring. Prenatal benzodiazepine use can exacerbate
neonatal abstinence syndrome (NAS) in the presence of opioid use disorder and
can cause seizures in the newborn. Neonatal benzodiazepine withdrawal
syndrome can present as floppy infant syndrome (hypotonia, hypothermia, and
suckling difficulties) or with tremors, irritability, hyperactivity, and cyanosis
(76). Severe benzodiazepine withdrawal symptoms during pregnancy can place
the fetus in distress, potentially causing miscarriage, and may induce preterm
labor.
All classes of benzodiazepines (and phenobarbital) cross the placenta and are
excreted in breast milk. Most have a pregnancy Category D rating (positive
evidence of human fetal risk), but the benefits from use in pregnant women may
be acceptable despite the risk. Four benzodiazepines (flurazepam, estazolam,
temazepam, and quazepam) have a Category X rating (contraindicated in
pregnancy). Taking into account the possible adverse effects to the growing
fetus, it is advised to limit the number of ancillary medications used in medically
assisted withdrawal. Studies on epileptic patients taking phenobarbital showed
an increased risk in congenital abnormalities but a later study showed that
phenobarbital use in patients without epilepsy did not seem to pose a significant
risk for congenital anomalies (77). It is therefore advised to use these
medications and taper down as quickly and safely as possible.
PATIENT EVALUATION AND

MANAGEMENT
Evaluation and Assessment
Evaluating patients for benzodiazepine cessation and withdrawal management
requires a combination of clinical, diagnostic, consultation and liaison,
counseling, and pharmacological management skills. To be effective, the
clinician must be flexible and able to tolerate ambiguities and variations in the
course of withdrawal while supporting the patient (who generally experiences
significant apprehension and anxiety). Clinical evaluation and assessment of the
patient typically include the following steps.
Step 1
Determine the reasons the patient or referral source is seeking evaluation of
sedative–hypnotic use and/or discontinuation. Determine the medical indications
for the sedative–hypnotic. If there is a referring or prescribing physician, a
discussion with that physician should occur to co-manage his or her sedative–
hypnotic treatment. Discussion with any other referring person or close family
members often is helpful. Seek evidence to answer the question as to whether the
patient’s use is improving his or her quality of life or is causing a significant
disability or helping or exacerbating the original condition. Discuss the patient’s
expectations.
Step 2
Take a sedative–hypnotic use history, including, at a minimum, the dose,
duration of use, substances used, and the patient’s clinical response to sedative–
hypnotic use at present and over time. The history should include attempts at
abstinence, including previous episodes of withdrawal , symptoms experienced
with changing the dose, and reasons for (and responses to) increasing or
decreasing the dose. The history should include behavioral responses to
sedative–hypnotic use and adverse or toxic side effects. For persons who used
sedative–hypnotics long term, clinicians should determine the clinical efficacy
and risks and benefits of sedative–hypnotic continuation or discontinuation.
Step 3
Elicit a detailed accounting of alcohol and other psychoactive drug use,
including medical and nonmedical use, prescribed and over-the-counter drug
use, current and past use, as well as the sequelae of such use. In addition to prior
withdrawal experiences, the history also should include prior periods of
abstinence and abstinence attempts.
Step 4
Take a psychiatric history, including current and past psychiatric diagnoses,
hospitalizations, suicide attempts, trauma history, prior treatment, psychotherapy,
and therapists (names and locations). Ask if alcohol or other drugs were used
during or near the time any psychiatric diagnoses were made. Ask if the referring
clinician was aware of any patient alcohol or other psychoactive substance use.
The Minnesota Multiphasic Personality Inventory may be helpful for the
dependence subscale scores. Early taper dropouts had higher Minnesota
Multiphasic Personality Inventory dependence subscale scores than did late taper
dropouts and completers of a taper (78). Personality assessments may help
identify patients who may be more suitable to attempt withdrawal. High levels of
dependency, passivity, neuroticism, and harm avoidance on the Minnesota
Multiphasic Personality Inventory contributed to increased withdrawal severity
(79).
Step 5
Take a family history of substance use, psychiatric, and medical disorders.
Step 6
Take a medical history of the patient, including illnesses, trauma, surgery,
medications, allergies, and history of loss of consciousness, seizures, or seizure
disorder. Some medications, such as beta-blockers, may mask withdrawal
symptoms or limit pharmacological intervention for withdrawal.
Step 7
Take a psychosocial history, including adverse childhood experiences, current
social status, and support system.
Step 8
Perform a physical and mental status examination.
Step 9
Conduct a laboratory urine drug screen for addictive substances. An alcohol
breath test (if available) often is helpful in providing immediate evidence of
alcohol use that was not disclosed in the history. Remember that these are
therapeutic tools. Trust the patient, but check the urine. Unfortunately, most
urine drug screens test for oxazepam and therefore only screen for
benzodiazepines that are metabolized to oxazepam. Such screens fail to identify
alprazolam, lorazepam, and clonazepam; these must be tested for specifically if
indicated. Depending on the patient’s profile, a complete blood count (CBC),
blood chemistry panel, liver enzymes, viral hepatitis panel, HIV test,
tuberculosis test, pregnancy test, or electrocardiogram test may be indicated.
Step 10
Complete an individualized assessment, taking into account all aspects of the
patient’s presentation and history and, in particular, focusing on factors that
would significantly influence the presence, severity, and time course of
withdrawal.
Step 11
Arrive at a differential diagnosis, including a comprehensive list of diagnoses
that have been considered. This greatly aids clinical management decisions as
the patient’s symptoms diminish, emerge, or change in character during and after
drug cessation.
Step 12
Determine the appropriate setting for withdrawal management. In addition to the
usual considerations for placement of any patient with the appropriate level of
care for addiction treatment, patients dependent on alcohol and sedative–
hypnotics or opioids and sedative–hypnotics should undergo medically assisted
withdrawal in an inpatient (24 hours medically monitored) setting due to risk of
sedation and overdose.
Step 13
Determine the most efficacious withdrawal management method. In addition to
proven clinical and pharmacological efficacy, the method selected should be one
that the physician and clinical staff in the withdrawal management setting are
comfortable with and experienced in administering.
Step 14
Obtain the patient’s informed consent.
Step 15
Initiate withdrawal management. Ongoing physician involvement is central to
appropriate management of withdrawal. Subsequent to the patient assessment,
development of the treatment plan, and obtaining patient informed consent, the
individualized discontinuation program should be initiated. The physician
closely monitors and flexibly manages, adjusting as necessary, the dosing or
withdrawal management strategy to provide the safest, most comfortable, and
efficacious course of withdrawal . To achieve optimal results, the physician and
patient should establish a close working relationship. A written and signed
withdrawal agreement can be a useful tool.
Management
Strategies for discontinuation fall into two categories: minimal intervention and
systematic discontinuation. Minimal intervention delivers simple advice to
discontinue the benzodiazepine. This can be done as part of an office visit, in a
letter to the patient, or in a group setting. Several studies have investigated this
tool and have found it effective in fostering benzodiazepine discontinuation.
Oude Voshaar et al. (80) reviewed 29 articles and found an improved odds for
discontinuation (odds ratio 2.8) by using a simple letter or group information
session. After receiving a letter with advice to quit gradually, 49% (53/109) of
patients using benzodiazepines did so in 30 general practice clinics maintained
abstinence for more than 2 years (819 ± 100 days) (81). Cormack et al. (82)
showed a two-thirds reduction in the benzodiazepine dose used by using a letter
advising the gradual reduction of the benzodiazepine. Minimal interventions are
more effective in patients prescribed low doses of sedative–hypnotic
medications.
Systematic Discontinuation
For patients who are dependent on sedative–hypnotics, there are two primary
options for the withdrawal management process: tapering or substitution and
tapering. Gradual dose reduction (tapering) is the most widely used and most
logical method of benzodiazepine discontinuation. The taper method is indicated
for use in an outpatient ambulatory setting, patients with therapeutic dose
benzodiazepine dependence, patients who are dependent only on
benzodiazepines, and patients who can reliably present for regular clinical
follow-up during and after withdrawal (50,62,69,78,83–88).
Tapering
With the taper method, the patient is slowly and gradually weaned from the
benzodiazepine on which he or she is dependent, using a fixed-dose taper
schedule. This is ideal if the benzodiazepine being used is long acting. The dose
is decreased on a weekly to every-other-week basis. The rate of discontinuation
for patients who used benzodiazepines for the long term (>1 year) should not
exceed 5-mg diazepam equivalents per week (12.5-mg chlordiazepoxide or 15-
mg phenobarbital equivalents) or 10% of the current (starting) dose per week,
whichever is smaller. The first 50% of the taper is usually smoother, quicker, and
less symptomatic than the last 50% (52,78). For the final 25%-35% of the taper,
the rate or dose reduction schedule should be slowed to half the previous dose
reduction per week and the reduction accomplished at twice the original tapering
interval. If symptoms of withdrawal occur, the dose could be increased slightly
until the symptoms resolve and the subsequent taper schedule commenced at a
slower rate.
Some patients may want to accelerate the reduction. This acceleration is
better tolerated and can be encouraged early in the reduction (78). In general,
patients tolerate more dose reduction and with shorter intervals early in the
tapering process and then require decreased dose reduction over longer intervals
as the taper progresses and the dose is reduced. A common error is trying to push
the taper process too quickly (86,87).
Brief office visits should be conducted at least weekly to facilitate regular
assessment of the patient for withdrawal symptoms, general health, taper
compliance, and use of supportive therapy. Standardized advice from the
physician doing the taper is an essential component (88). Taper medications
should be closely controlled by prescribing an amount sufficient only for the
time until the next visit. The prescriber should give a clear message to the patient
that lost, misplaced, or stolen medication will invoke a reevaluation of the
current treatment plan and could lead to an alternative discontinuation paradigm
and/or higher level of care. A written withdrawal agreement between the patient
and clinician, signed by the patient, is strongly advised. A copy of the written
schedule of daily doses, covering multiple weeks to months, may help the patient
adhere to the reduction plan. A reliable support person who is in daily contact
with the patient is very helpful. The patient will need to give written consent for
contacting the support person.
Patients who are unable to complete a simple taper program should be
reevaluated and, if indicated, an alternative withdrawal management method
and/or higher level of clinical care chosen. Some patients may require a
substitution and taper program or a period of hospitalization to receive more
intensive monitoring and support to complete drug discontinuation.
Substitution and Taper

Substitution and taper methods employ cross-tolerant long-acting
benzodiazepines (such as chlordiazepoxide or clonazepam) or phenobarbital to
substitute, at equipotent doses, for the sedative–hypnotics on which the patient is
dependent (Table 52-3). Chlordiazepoxide, clonazepam, and phenobarbital are
the most widely used substitution agents for a number of important reasons:
TABLE 52-3 Sedative–Hypnotic Withdrawal

Substitution Dose Conversions
At steady state, there is negligible interdose serum level variation with these
medications; with tapering, there is a more gradual reduction in serum
levels, reducing the risk that withdrawal symptoms will emerge.
Each of the medications has low addictive potential (phenobarbital and
chlordiazepoxide are lowest followed by clonazepam). While this point is
generally accepted, there is regional variability in this potential. For
example, anecdotally, clonazepam is often misused in the Northeast and is
particularly popular among patients in opioid agonist treatment and with
opioid use disorder.
Phenobarbital offers the added advantage of rarely inducing behavioral

disinhibition and possesses broad clinical efficacy in the management of
withdrawal from all classes of sedative–hypnotic agents. Clinical experience
shows that phenobarbital is most useful and effective in patients with
dependence on more than one drug, in patients with high-dose dependence, and
in patients with unknown dose or erratic “polypharmacy” drug use.
Benzodiazepines need GABA to work. Because in chronic benzodiazepine
use GABA production is down-regulated and GABA receptors are altered in
expression, phenobarbital is a better option to manage withdrawal symptoms.
Barbiturates directly activate GABAA receptors, resulting in prolonging the
duration that chloride channels remain open.
With impaired hepatic function or elevated liver tests, oxazepam may be a
good substitute (69). Lorazepam could be considered, but its addiction liability is
higher than that of oxazepam (68). However, if a patient is in an inpatient setting
with close monitoring, one can use longer-acting agents while monitoring for
sedation and adjusting dosing accordingly.
Uncomplicated Substitution and Taper

This method is used in outpatient settings for patients who are discontinuing use
of short half-life benzodiazepines or for those who are unable to tolerate gradual
tapering:
1. Calculate the equivalent dose of chlordiazepoxide, clonazepam, or

phenobarbital using the Substitution Dose Conversion Table (Table 52-3).
Individual variation in clinical responses to “equivalent” doses can vary, so
close clinical monitoring of patient response to substitution is necessary.
Adjustments to the initially calculated dose schedule are to be expected.
2. Provide the substituted medication in a divided dose. For chlordiazepoxide,
oxazepam, or phenobarbital, give three to four doses per day. For
clonazepam, two to three doses per day usually are sufficient.
3. Provide the patient with smaller as-needed (PRN) doses of the substituted
medication. This will help to suppress breakthrough symptoms of
withdrawal. Do this for the first 2-3 days only, and then discontinue PRN
dosing. Be cautious and conservative on the amount of benzodiazepine
given while being mindful that undertreatment is the main reason for
treatment failure at this stage. Avoid using different types of
benzodiazepines concurrently as it makes it difficult to identify the
stabilizing dose and increase a patient’s risk of overdose. A rescue dose of
intermediate-acting benzodiazepine (lorazepam) may be used in the setting
of severe withdrawal symptoms or risk of impending seizure as a bridging
dose until the long-acting medication takes effect. Do not use phenobarbital
in combination with benzodiazepines in an outpatient setting.
4. Stabilize the patient on an adequate substitution dose (same dose on
consecutive days without the need for regular PRN doses). This usually is
accomplished within 1 week.
5. Gradually reduce the dose. The dose is decreased on a weekly to every-
other-week basis, as in the simple taper model. The rate of discontinuation
is 5-mg diazepam equivalents per week (or 12.5-mg chlordiazepoxide
equivalents or 15-mg phenobarbital equivalents), as shown in Table 52-3, or
10% of the current (starting) dose per week. The first half of the taper
usually is smoother, quicker, and less symptomatic than the latter half.
6. For the final 25%-35% of the taper, the rate, or dose reduction, should be
slowed. This may be a good time to introduce ancillary medications such as
gabapentin into the treatment regimen. If symptoms of withdrawal occur,
hold the taper for 3-4 days to stabilize the patient, and then resume the
process. Some patients may wish to accelerate the reduction. This is better
tolerated early in the taper. Care should be taken not to push the taper too
quickly.
7. Support the patient with short but frequent visits, as described above. Taper
medication should be closely controlled by prescribing only enough
medication for the time period until the next visit.
Phenobarbital Induction and Taper Protocol

Based on the Sedative–Hypnotic Tolerance Test developed by Drs. Smith and
Wesson (40–42), this protocol is ideal when the degree of dependence is difficult
to determine. Such a situation is common in high-dose, erratic-dose, illicit
source, “polysubstance,” or alcohol plus sedative–hypnotic use. It is best done in
a setting that offers 24-hour medical monitoring. Phenobarbital is used because
of the adaptive changes that occur with chronic benzodiazepine use discussed
previously. Also it boasts rapid onset of action, long half-life, and ease with
which signs of toxicity can be monitored:
1. A 60-mg phenobarbital dose is given orally every 2 hours PRN CIWA-Ar >
15 for up to 48 hours.
2. Doses are held for signs of toxicity (intoxication), which develop in the
following progression at increasing serum levels: fine lateral sustained
nystagmus, coarse nystagmus, slurred speech, ataxia, and somnolence.
Doses are held with the development of coarse nystagmus and slurred
speech and subsequently resumed with the resolution of the signs of
toxicity.
3. The patient is monitored hourly to ensure adequate dosing and to prevent
oversedation. Ideally, a balance is achieved between the signs and
symptoms of withdrawal and those of phenobarbital intoxication.
4. After 48 hours, the total amount of administered phenobarbital is divided by
the number of days it was administered. This amount is the 24-hour
stabilizing dose that was administered in the first 48 hours to stabilize the
patient.
5. The taper is started after the first 48 hours of stabilization by reducing the
stabilizing dose by 20%-30% every day for the first half of the taper and a
gentler 10% every other day for the second half of the taper.
6. The total daily dose should be divided so that the largest dose is
administered in the evening to help with sleep while avoiding sedation
throughout the day.
Example of Phenobarbital Taper

If the total 48-hour dose is 600 mg, then the 24-hour stabilizing dose is 300 mg.
The initial taper dose would be 210-240 mg (correlate with clinical
presentation to guide dose choice).
The taper may be extended or decreased depending on patient’s presentation.
Patients often can be transferred from an inpatient setting to an intensive
(medically monitored) outpatient program after they are stabilized and well
established on the tapering portion of the protocol.
Combination Therapy Using Anticonvulsants and

Phenobarbital
While acute benzodiazepine withdrawal can be managed with a combination of
anticonvulsants and phenobarbital in an inpatient setting, it is falling out of favor
because of adverse effects of the anticonvulsants and increased risk of
medication interactions. An example of such a protocol appears here:
1. Phenobarbital is begun with a loading dose of 60 mg orally every 4 hours

for 4 or 5 doses. This is followed by a maintenance dose of 60 mg four
times per day for 2 days and then 30 mg four times per day for 1 or 2 days.
For elderly (over 60 years of age) or in compromised health, start with a
loading dose of 30 mg every 4 hours for 4-5 doses, followed by 30 mg four
times per day for 3-4 days.
2. An anticonvulsant is started at the same time as the phenobarbital.
Commonly used anticonvulsants are carbamazepine, sodium
valproate/valproic acid, and gabapentin. Carbamazepine is started at 200
mg three times per day, sodium valproate/valproic acid is started at 250 mg
three times per day, and gabapentin is started at 300 mg three times per day.
All have similar efficacy. Gabapentin seems to have the lowest side effect
profile. Anticonvulsants can be continued for 2-4 weeks after acute
withdrawal management and then tapered; longer use of these agents could
be considered on a case-by-case basis. Physical observation (sedation, rash)
and laboratory monitoring (CBC, liver function tests [LFTs]) are indicated
with use of these medications past several weeks.
3. Breakthrough withdrawal occurring in the first few days to 1 week can be
effectively treated with a short course (2-3 days) of a long half-life
benzodiazepine such as chlordiazepoxide (25 mg three times per day for 1
day, followed by 25 mg two times per day for 1 day, and then 25 mg one
time on the third day). Breakthrough withdrawal occurring after the first
week and usually when phenobarbital has stopped can be treated with a
short course of low-dose phenobarbital (30-60 mg/d divided into 2-3
doses), which is then tapered over 5-7 days.
Another point of concern is that phenobarbital and carbamazepine are both

strongly associated with Stevens-Johnson syndrome and their concomitant use
may markedly increase this risk.
Appropriate Clinical Setting

Patients who have dependence on multiple substances (including sedative–
hypnotics), mixed alcohol and other sedative–hypnotic use, high-dose sedative–
hypnotic use, erratic behavior, incompatible/unreliable substance use histories,
involvement with illicit sources, and extensive mental health issues are best
served in an inpatient facility that offers 24-hour medical monitoring.
Adjunctive Withdrawal Management

Measures
Anticonvulsants
Since the 1980s, anticonvulsants have been studied and used to treat sedative–
hypnotic withdrawal, especially benzodiazepine withdrawal. The use of
anticonvulsants grew from the success of treating certain psychiatric disorders
and the improved understanding of kindling mechanisms for withdrawal. Some
anticonvulsants were also beneficial in treating alcohol withdrawal and cocaine
intoxication. There appears to be no addiction potential with anticonvulsants,
and this is a great advantage (89).
Carbamazepine
Carbamazepine’s actions have been associated with the neurotransmitters
serotonin, GABA, excitatory amino acids, and glutamate (89–92). It inhibits
glutamate release. Adjunctive carbamazepine therapy is not widely used,
although clinical protocols and patient selection for this method have been
studied. Initial reports on small clinical trials using carbamazepine showed
encouraging but mixed effectiveness and utility (59,93–97). Pages and Ries (98)
reviewed further use of carbamazepine and found it to be an effective adjunct.
Schweizer et al. (92) studied 40 patients with a history of difficulty discontinuing
long-term therapeutic benzodiazepines. Significantly, more patients treated with
carbamazepine were benzodiazepine-free at 5 weeks. Patients receiving
carbamazepine (but not the clinicians evaluating them) reported a larger
reduction in withdrawal severity compared with patients taking placebo.
Ries et al. (94) and Pages and Ries (98) reported protocols for the use of
carbamazepine: 600 mg/d (usually 200 mg three times per day) is used alone or
in combination with a 3-day benzodiazepine taper. Chlordiazepoxide is useful
because of its longer half-life and low potential for misuse. Phenobarbital can be
added PRN to this protocol for breakthrough withdrawal symptoms.
Carbamazepine is continued for a minimum of 2-3 weeks after the 3-day
benzodiazepine taper is completed and can be tapered to monitor for return of
withdrawal symptoms. Elderly patients who are discontinuing benzodiazepines
have been treated successfully with carbamazepine at doses of 400-500 mg/d.
Adverse consequences of carbamazepine use can include gastrointestinal
upset, neutropenia, thrombocytopenia, and hyponatremia, necessitating initial
and ongoing laboratory evaluation and monitoring. In pregnancy, it is a risk
Category D and should be avoided during the first trimester because of the risk
of neural tube defects.
Sodium Valproate
Reports indicate that sodium valproate is effective in attenuating the
benzodiazepine withdrawal syndrome. Valproate possesses GABAergic actions
and anticonvulsant effects (99,100). It is believed to increase brain GABA
concentrations by unknown mechanisms. Valproate also may suppress NMDA
and reduce L-glutamate responses (92,99,101). Rickels et al. (102) found that
although valproate did not reduce acute withdrawal severity, valproate-treated
patients were 2.5 times more likely to be benzodiazepine-free at 5 weeks after
taper, compared with a placebo group.
Valproate doses of 250 mg three times per day (250 mg two times per day if
older than age 60) can be used in combination with a 3-day benzodiazepine
taper. Chlordiazepoxide is a useful choice because of its long half-life and low
addictive potential. Calculate the equivalent chlordiazepoxide dose for the
amount of current benzodiazepine being discontinued. Give one-half to two-
thirds of this dose spaced equally (divided in two to three doses) over the first
day (24 hours), one-third spaced equally over the second day (second 24 hours),
and 10%-20% spaced equally over the third day (third 24 hours). Phenobarbital
can be used for breakthrough withdrawal symptoms. Valproate is continued for a
minimum of 2-3 weeks after the 3-day benzodiazepine taper is completed.
Longer treatment may improve the proportion of patients who remain
benzodiazepine-free. Valproate can be tapered to monitor for return of
Valproate has been used to treat anxiety. It has fewer side effects than
carbamazepine. It can be used both inpatient and outpatient. For these reasons,
further studies may strengthen the role of valproate in the treatment of
benzodiazepine withdrawal. Side effects (including elevated LFTs,
thrombocytopenia, bone marrow suppression, and pancreatitis), drug reactions
(including rash and erythema multiforme), gastric upset, and behavioral changes
require close monitoring. Like carbamazepine, it is a Category D drug in
pregnancy, and its use in the first trimester is associated with increased risk of
neural tube defects.
Gabapentin
By binding to the alpha-2/delta subunit of voltage-sensitive calcium channels,
gabapentin closes N and P/Q presynaptic calcium channels, diminishing
excessive neuronal activity and neurotransmitter release. It is structurally related
to GABA, but there are no known direct actions on GABA or its receptors. It is
useful as adjuvant therapy in alcohol and benzodiazepine withdrawal. Unlike
carbamazepine and valproate, gabapentin is a pregnancy Category C medication.
It still should be avoided during pregnancy but appears to be a safer option. Of
note, however, its addictive potential in people with addiction has been recently
recognized, which may limit some of its advantages.
Gabapentin, topiramate, and lamotrigine have been tried in several small
studies. Gabapentin seems to be interchangeable with carbamazepine and with
sodium valproate/valproic acid. Lamotrigine is limited by its need for a slow
buildup in dose. Most of the studies using these anticonvulsants involved
patients with alcohol use disorder. More studies are needed (89,103–105).
Flumazenil
Flumazenil is useful for complications of acute intoxication with
benzodiazepines as discussed earlier in this chapter. Caution must be used as it is
capable of causing marked withdrawal symptoms and seizures. Flumazenil is not
useful as an adjunct to tapering. Because of its weak agonist properties, it may
be useful to reduce cravings after the tapering is complete (106). Flumazenil’s
antagonist properties may help prevent relapse, but no studies support this
indication.
Propranolol
Tyrer et al. (49) clearly demonstrated that propranolol alone does not affect the
rate of successful benzodiazepine discontinuation or the incidence of withdrawal
symptoms for discontinuation of chronic benzodiazepine use. However,
propranolol treatment did diminish the severity of adrenergic signs and
symptoms of withdrawal. Propranolol is not cross-tolerant with sedative–
hypnotic medications and should not be used as the sole therapeutic agent in
managing sedative–hypnotic withdrawal. Propranolol can be used, in doses of
60-120 mg/d, divided three or four times per day, as an adjunct to one of the
aforementioned withdrawal methods, when additional control of autonomic
signs and symptoms is deemed important. However, clinicians need to be
mindful that propranolol treatment will diminish some of the very symptoms and
signs that are monitored to determine substitution doses. One must be mindful of
side effects such as weight gain, sedation, and depression.
Clonidine
Clonidine has been shown to be ineffective in treating benzodiazepine
withdrawal. Doses sufficient to decrease serum levels of norepinephrine
metabolites had minimal attenuating effect on the benzodiazepine withdrawal
syndrome. One significant result of this study was the demonstration that
increased norepinephrine activity plays a small role in the overall
benzodiazepine withdrawal syndrome. In some cases when autonomic
dysregulation persists after acute withdrawal, clonidine can be used to control
symptoms in the post-acute withdrawal state.
Buspirone
Buspirone is a nonbenzodiazepine anxiolytic medication that is not cross-
tolerant with benzodiazepines or other sedative–hypnotic medications.
Schweizer and Rickels (107) and Ashton et al. (108) demonstrated that
buspirone substitution in patients undergoing abrupt or gradual benzodiazepine
discontinuation failed to protect against the symptoms of withdrawal.
Trazodone
Trazodone is useful in the management of benzodiazepine withdrawal.
Trazodone decreased anxiety in benzodiazepine-tapered patients (109).
Trazodone improved patients’ ability to remain benzodiazepine-free after a 4-
week taper of the benzodiazepine. In one study, two-thirds of the patients treated
with trazodone, compared with 31% of patients treated with placebo, were
benzodiazepine-free at 5 weeks after taper (102). Trazodone can be used to
improve sleep during benzodiazepine tapering and when benzodiazepine-free.
Side effects may include dry mouth, morning hangover, drowsiness, dizziness,
and priapism.
Mirtazapine
Mirtazapine has been used in a similar way as trazodone and found to be useful
(110).
Cognitive–Behavioral Therapy
Two studies (111,112) demonstrate that, in patients with panic disorder, adding
cognitive–behavioral therapy (CBT) to alprazolam discontinuation improved the
rate of successful alprazolam discontinuation. Spiegel et al. (111) reported that
patients in the combined taper and CBT groups had greater rates of abstinence
from alprazolam at 6 months than did those who underwent taper alone. A
cognitive group approach improved attrition rates and long-term outcomes for
benzodiazepine withdrawal (113). Oude Voshaar et al. (114) reported that adding
cognitive–behavioral group therapy did not improve benzodiazepine
discontinuation success.
Patients must maintain abstinence from benzodiazepines in spite of
recurrences of the symptoms of the disorder that led to benzodiazepine use.
Benzodiazepine tapering must be completed before psychological treatment
concludes. Cognitive–behavioral treatment can support the withdrawal taper and
help with exacerbations of the initial disorder (115). Of note, it is important to
consider psychosocial therapy for the underlying disorder that was the indication
for the benzodiazepine in the first place.
Prolonged Benzodiazepine Withdrawal

Some physicians report (40–42), and clinical experience confirms, that a small
proportion of patients, after long-term benzodiazepine use, experience a
prolonged syndrome in which withdrawal signs and symptoms persist for weeks
to months after discontinuation. This prolonged withdrawal syndrome is noted
for its irregular and unpredictable day-to-day course and qualitative and
quantitative differences in symptoms from both the prebenzodiazepine use state
and the acute withdrawal period. Patients with prolonged withdrawal often
experience slowly abating, albeit characteristic, waxing and waning symptoms
of insomnia, perceptual disturbances, tremor, sensory hypersensitivities, and
anxiety.
Smith and Wesson (40) propose that protracted symptoms reflect long-term
receptor site adaptations. Higgitt and Fonagy (116) propose that a
comprehensive etiological model of the prolonged syndrome must include a
psychological component that can be explained through cognitive and behavioral
models. They observe that many patients with persistent withdrawal symptoms
resemble patients with somatization disorders. The patients often experience
acute withdrawal more severely and may be “sensitized to anxiety.” In addition
to a potential lack of effective coping mechanisms away from benzodiazepines,
such patients often possess a perceptual or cognitive style that leads to
apprehensiveness, body sensation amplification and mislabeling, and
misinterpretation.
Management
Before entertaining the existence of a prolonged withdrawal syndrome,
physicians must rule out psychiatric conditions. A distinguishing characteristic
of protracted withdrawal from anxiety disorders is the gradual diminution and
eventual resolution of symptoms with benzodiazepine withdrawal.
Propranolol in doses of 10-20 mg four times per day often is helpful in
attenuating anxiety or tremors. Extended use of anticonvulsants with eventual
slow tapering should be considered. Gabapentin is well tolerated and helps
relieve anxiety and insomnia. Start with 100-300 mg three times a day and
increase dose every week depending on symptomatology. A higher dose in the
evening to help with insomnia may be advised. Lower doses of sedating
antidepressant medications—such as trazodone, amitriptyline, imipramine, or
doxepin—are helpful in treating insomnia. Frequent clinical follow-up for
education, supportive psychotherapy, and regular reassurance are strongly
advised. Frequent reassessment of the working diagnosis is recommended.
COMMON TREATMENT ISSUES

Treatment is indicated for nearly all patients with substance use disorders.
Among persons with sedative–hypnotic dependence, treatment most often is
indicated for those who use multiple substances, use high-doses, or patients in
whom addiction is diagnosed. The support, education, and recovery training
available in most addiction specialty treatment programs are valuable to many
patients who are dependent on sedative–hypnotics. On the other hand, patients
with long-term, therapeutic use problems should not be coerced to participate in
specialty programs designed to treat substance use disorder, as they often feel
out of place and unable to relate to their peers.
Participation in specific components of treatment, tailored to each patient’s
individual needs, can be helpful and nonthreatening. Patients who choose to
participate in treatment often discover an immense source of support and
encouragement, in addition to learning and practicing coping skills that facilitate
drug discontinuation and abstinence.
Prevention
The best prevention for licit (prescribed) benzodiazepine dependence is careful
prescribing (85,86). In England, the Committee on the Review of Medicines
reported in 1980 that the hypnotic effect of benzodiazepines diminishes after 3-
14 days and the anxiolytic effect diminishes after 4 months (20). A good
understanding of the mental health disorders with anxiety symptoms and their
psychological and pharmacological therapies is important. Knowledge of a
patient’s risk factors for addiction, including his or her family’s substance use
disorder history is also important. Benzodiazepines are rarely the first-line
treatment for any of the anxiety disorders. CBT, group therapy, relaxation
therapy, stress management, structured problem solving, selective serotonin
reuptake inhibitors, tricyclic antidepressants, and buspirone are all potential
options that should be employed as appropriate based on the level of severity. If
used, benzodiazepines should be closely monitored for effectiveness and
duration. A plan to reassess or taper the benzodiazepine when it is first given is
wise. Reevaluate the need for the benzodiazepine when the initial indication has
changed or the patient shows improvement (85,117). A benzodiazepine taper
should be strongly considered in the long-term management of chronic anxiety
with benzodiazepines even if it is only useful to determine whether continued
treatment is required or not (78).
SUMMARY
Sedative–hypnotics are among the most extensively prescribed medications in
the United States. They are widely used and misused; hence, they are the second
most frequently reported drug class to cause emergency department visits,
surpassed only by opioids. They utilize the same biochemical and neurological
pathways as alcohol, have similar dependence and withdrawal characteristics,
and exhibit cross-tolerance. Intoxication is characterized by impaired motor
activity and immediate memory impairment and may progress to stupor and
coma. Toxicity associated with older nonbenzodiazepine medications is
progressive and can ultimately lead to respiratory arrest or cardiovascular
collapse, while benzodiazepines and Z-drugs do not cause death unless used in
combination with other CNS depressants (such as alcohol or opioids).
Their use can result in physical dependence and abrupt abstinence leads to a
withdrawal syndrome that can be life-threatening. Benzodiazepine withdrawal
syndromes are similar to that of alcohol. Benzodiazepine withdrawal is
characterized by autonomic hyperactivity and can lead to seizures and death.
Treatment of sedative-hypnotic withdrawal can be achieved by either gradual
tapering of the drug or symptom-driven substitution with phenobarbital or a
long-acting benzodiazepine. Other medications may have an ancillary role in
treatment but are not indicated as monotherapy.
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CHAPTER 53
Management of Opioid Intoxication and
Withdrawal
Jeanette M. Tetrault and Patrick G. O’Connor
CHAPTER OUTLINE
Introduction
Opioid Intoxication and Overdose
Opioid Withdrawal
Conclusions
INTRODUCTION
Opioids include substances that are derived directly from the opium poppy (such
as morphine and codeine), the semisynthetic opioids (such as heroin), and the
purely synthetic opioids (such as methadone and fentanyl).
These compounds share several pharmacological effects, including sedation,
respiratory depression, and analgesia, and common clinical features of
intoxication and withdrawal. This chapter reviews the clinical features of opioid
intoxication and withdrawal.
Although all drugs in the class are associated with clinical withdrawal
syndromes, those most commonly encountered in clinical practice include
heroin, methadone, morphine, oxycodone, codeine, hydrocodone, and
meperidine (1).
OPIOID INTOXICATION AND

OVERDOSE
Clinical Picture
The prevalence of opioid use in the United States continues to increase.
According to the results of the National Survey on Drug Use and Health, among
individuals 12 years of age or older, self-reported lifetime heroin use has
increased from 1.2% in 2000 to 1.9% in 2015 (1). Similarly, there has been an
increase in the lifetime nonmedical use of prescription opioids among
individuals 12 years of age and older from 8.6% in 2000 to 13.6% in 2014. After
2014, there was a change in methodology of the National Survey of Drug Use
making it challenging to make comparisons for certain questions (1,2). Opioid
intoxication and overdose may present in a variety of settings. Although mild-to-
moderate intoxication, characterized by euphoria or sedation, usually is not life
threatening, severe intoxication or overdose is a medical emergency that causes
many preventable deaths and thus requires immediate attention (3). Opioid
overdose is characterized by the classic signs of depressed mental status,
decreased respiratory rate, decreased bowel sounds, and miotic pupils. In a
retrospective analysis of consecutive cases of presumed opioid overdose in
patients initially managed by emergency medical services personnel in an urban
setting, 16% were either dead or in full cardiopulmonary arrest at the time of the
initial emergency medical service evaluation (4). As the prevalence of opioid use
has increased in the United States, the incidence of opioid overdose has
increased as well. Among almost 48,000 substance related overdose deaths that
occurred in the United States in 2014, 61% were due to opioids and opioid death
rates increased by 15.6% from 2014 to 2015 (5). Additionally, for patients
prescribed opioids for chronic, noncancer pain, overdose risk increases in a
dose-dependent fashion. Of 9,940 patients receiving prescription opioids in a
managed care organization from 1997 to 2005, 51 overdoses were noted, 6 of
which were fatal. Compared to patients receiving 1 to 20 mg/d of morphine
equivalents, those receiving 50 to 99 mg/d had a 3.7-fold increased risk of
overdose, and those receiving 100 or more mg per day had an 8.9-fold increase
in overdose risk (6). Accidental overdose may occur in a variety of settings. Of
increasing concern are accidental overdoses occurring in several US cities where
heroin or other substances are mixed with more potent opioids (eg, fentanyl)
(7–10). Despite these increases, opioid overdose can be treated successfully, if
patients present in a timely manner and general principles of overdose
management (as well as specific therapies for opioid overdose) are employed. In
a retrospective analysis in Finland, the survival-to-hospital discharge rate of
cardiopulmonary arrest after heroin overdose (16%) was found to be similar to
that of other poisonings (11%) (11).
Nonfatal opioid overdose is an additional cause of significant morbidity, and
the true prevalence may not be well understood because many nonfatal
overdoses are not brought to medical attention (12). The prevalence of nonfatal
overdose ranged from 10% to 69% as reported in recent literature (12). The
factors associated with nonfatal opioid overdose include injection as the route of
administration, sporadic heroin use, needing help with injection, prior overdose,
and multiple drug use.
The pharmacological actions responsible for opioid intoxication and
overdose involve central nervous system (CNS) mu, kappa, and delta opioid
receptors (13,14) that also interact with endogenous substances, including the
endorphins (15). Of primary concern in the management of overdose are
interactions with mu receptors, which can lead to sedation and respiratory
depression. The mechanism of respiratory depression with opioids presumably is
direct suppression of respiratory centers in the brain stem and medulla (14).
The level of tolerance to opioids can have a significant effect on an
individual’s risk of opioid overdose. In addition, tolerance to respiratory
depression may be slower than tolerance to euphoric effects, thus explaining
why overdose occurs so often, even among “experienced” opioid users (16,17).
Patients who have undergone medically supervised withdrawal or those who
have experienced intentional or unintentional abstinence from opioids for any
reason (eg, incarceration) may be particularly susceptible to death from heroin
overdose (18–20). Nonfatal overdose is also common among patients
undergoing medically supervised withdrawal—occurring in 27% of a cohort of
201 patients with opioid use disorder patients followed for 2 years after
withdrawal. Among this group, prior overdose attempts and depressive
symptoms were risk factors for nonfatal overdose (21). Although injecting
opioids may be the route of administration associated with the highest risk of
overdose, increasingly popular noninjection routes are associated with
significant risk as well (22). Additionally, case reports of fatal opioid overdose
among opioid-naive patients who use cocaine have been published whereby
these patients have unknowingly used pure fentanyl instead of cocaine (7).
Persons who administer opioids of potency that they are unaccustomed to may
experience opioid overdose. Finally, patients who administer opioids in addition
to other substances known to exacerbate the opioid effect (eg, benzodiazepines,
sedatives) may be more prone to overdose.
Diagnosis
As with most clinical challenges, evaluation of opioid intoxication begins with
the collection of patient data through a detailed history and physical examination
(Table 53-1). An important issue in the patient with moderate to severe
respiratory depression is the immediate institution of pharmacological and
supportive therapies to ameliorate morbidity and prevent mortality.
TABLE 53-1 Diagnosis of Opioid Overdose

ause multiple sources of information (family, hospital recrods,etc) to obtain complete history.
When available, historical information can be obtained concerning opioid use

(including the specific drug, amount, and time of last use) either directly from
the patient or from friends and family members; this information can supplement
available hospital records. In addition to opioids, it is important to ask about use
of other drugs or alcohol because of the likelihood use of more than one drug
(23–25). Identification of multiple drug use has important implications for
patient management; for example, identification of the frequent co-occurrence of
opioid and benzodiazepine overdose may indicate the need for additional therapy
directed at reversing the benzodiazepine component of the overdose with
flumazenil (26,27). This also is true in cases of suspected opioid overdose in
children who are at high risk of co-occurring opioid and benzodiazepine toxicity
and who thus may require management of both on presentation for medical care
(28). Multiple drug overdose often accounts for significant morbidity and
mortality. More than half of all drug overdose deaths result from multiple drug
overdose with opioids, alcohol, and cocaine (29,30).
Physical examination of the opioid-intoxicated patient may find CNS and
respiratory depression, as well as miosis and direct evidence of drug use, such as
needle tracks or soft tissue infection. The heroin overdose syndrome, described
as a triad of altered mental status, depressed respiration, and miotic pupils, has a
sensitivity of 92% and a specificity of 76% for the diagnosis of heroin overdose
(3). Additional evidence supports the use of clinical characteristics in the
diagnosis of heroin overdose. In a study of 730 patients in Los Angeles receiving
naloxone for suspected heroin overdose, the presence of one of the three clinical
signs—respirations <12 per minute, presence of pinpoint pupils, and
circumstantial evidence of opioid use—had a sensitivity of 92% and a specificity
of 76%, whereas the sensitivity of naloxone response was 88%, and specificity
was 86% (31). The laboratory can also provide important supportive information
in the evaluation of opioid intoxication, including urine toxicology testing for
naturally occurring and synthetic opioids. Be aware that often drug testing for
“opiates” is limited to derivatives of the opium poppy and may not include the
wider array of “opioids” (semisynthetic and synthetic opioids).
It is important to consider the differential diagnosis in patients presenting
with symptoms of opioid intoxication. Other possibilities of depressed mental
status include hypoglycemia, acidemia or other fluid and electrolyte disorders, or
complications from end-stage liver disease. Additionally, acute mental status
changes from HIV-related opportunistic infections may mimic those of opioid
intoxication (32). Although, overall, HIV incidence is decreasing, outbreaks
among people who inject drugs are of concern (33). Finally, intoxication from
other substances should be considered. Therefore, toxicology testing should be
performed immediately in emergency settings. Urine toxicology is preferred,
because urine contains higher concentrations of drugs and their metabolites than
serum. Results usually are qualitative, indicating only the presence or absence of
specific substances. Even when the results of toxicological screening are not
available until after acute management has been initiated, drug testing may
support the diagnosis of drug intoxication and also may reveal the presence of
other drugs not suspected on initial evaluation. Benzodiazepine misuse is
common among patients with opioid misuse and opioid use disorder, and some
benzodiazepines (such as clonazepam) may not be readily detectable by standard
urine toxicology testing. Alternative approaches involving the examination of
serum may be useful in documenting benzodiazepine use (34).
Kellermann et al. (35) examined the effects of drug testing on suspected
overdose in a study of 405 adult patients who presented to an emergency
department. Although initial clinical management did not change significantly
on the basis of the toxicology results, implications for treatment beyond the
acute event were noted. Poor follow-up of drug testing also was demonstrated in
a study of alcohol intoxication in patients injured in motor vehicle crashes. In
that study, none of 47 patients who had alcohol levels between 200 and 500
mg/dL were referred for a follow-up visit to address their alcohol use (36). Thus,
toxicology testing is useful not only for acute management but also for planning
care after discharge from the acute setting (37). Referral to alcohol and drug
treatment programs from the emergency department may be an effective
mechanism to link patients with opioid use disorder, who otherwise may not
interface with the medical system, with available treatment programs (38).
Although the emergency department presents a unique opportunity to screen
patients for substance use and link them to appropriate care, engagement in care
often proves challenging (39). Therefore, unique models of emergency
department initiation of opioid agonist treatment with direct linkage to care
should be developed, tried, and studied as they hold significant promise (40).
Opioid use and overdose also may be complicated by the effects of
substances employed to “cut” drugs purchased on the street. Along with inert
substances present to add bulk, active substances—including dextromethorphan,
lidocaine, and scopolamine—may be present. Additionally, unusual
complications may present as a result of contamination of illicit substances. For
instance, recent case reports of patients presenting with cutaneous necrosis,
purpura, and neutropenia have been linked to levamisole (an antihelminthic,
immunomodulatory, and antineoplastic medication)-contaminated cocaine (41).
Although the classic “triad” of respiratory depression, coma, and pinpoint
pupils usually alerts clinicians to the possibility of opioid overdose, atypical
presentations may cause some initial confusion. In a study of 43 hospitalized
patients who received naloxone for a clinically suspected opioid overdose, only
two patients had the classic triad, suggesting that a high index of suspicion
should be maintained in patients who may have atypical presentations (42).
Management
In a case of suspected severe opioid intoxication, resulting in overdose, general
supportive management must be instituted simultaneously with the specific
antidote, naloxone (Table 53-2) (3). Opioid overdose is characterized by the
classic signs of depressed mental status, decreased respiratory rate, decreased
bowel sounds, and miotic pupils. Individuals who present with signs and
symptoms of mild-to-moderate opioid intoxication without overdose can be
monitored and treated supportively without naloxone administration. Adult basic
life support and adult advanced cardiac life support need to be available (43,44).
The clinician needs to assure that an adequate airway is established and that
respiratory and cardiac function are appropriately assessed and managed.
Adequate intravenous access is essential so that fluids and pharmacological
agents can be administered as needed. Finally, frequent monitoring of vital signs
and cardiorespiratory status is required until it is clearly established that the
opioid and any other intoxicating substances have been cleared from the
patient’s system. Additionally, the clinician must consider the half-life of the
ingested substance as multiple doses of naloxone or an intravenous naloxone
drip may need to be instituted in the case of ingesting of a long-acting opioid.
TABLE 53-2 Management of Opioid Overdose

In the course of managing patients with suspected opioid overdose, clinicians
need to be aware of the co-occurrence of acute medical conditions and the
exacerbation of chronic medical conditions often seen in this population (32,45).
For example, prolonged hypoxia in overdose survivors can result in
rhabdomyolysis and myocardial infarction (46). Other issues, such as acute
infections, trauma, and chronic liver disease (including chronic hepatitis C virus
[HCV] infection), may have major implications for management of the overdose
patient (45).
Pharmacological Therapies
When a patient presents to an emergency department with miosis and respiratory
depression, pharmacological therapy for opioid overdose should be instituted
immediately (3). Naloxone hydrochloride, a pure opioid antagonist, can
effectively reverse the CNS effects of opioid intoxication and overdose. An
initial intravenous dose of 0.4 to 0.8 mg will quickly reverse neurological and
cardiorespiratory depression. The onset of action of intravenously administered
naloxone, as manifested by antagonism of opioid overdose, is ~2 minutes.
Although intravenous naloxone should work more rapidly than subcutaneous
naloxone, one study demonstrated that the subcutaneous route may be just as
effective for managing patients before they arrive in the emergency department;
additionally, the slower absorption time of the subcutaneous route may be
compensated for by the delay in establishing adequate intravenous access (47).
Intranasal naloxone, dosed at 2 mg, can be used effectively to reverse opioid
overdose in both the prehospital and hospital settings (48,49).
Overdose with opioids that are more potent (such as fentanyl) or longer
acting (such as methadone) may require higher doses of naloxone given over
longer periods of time, as by ongoing naloxone infusion (50). In patients who do
not respond to multiple doses of naloxone, alternative causes of the failure to
respond must be considered, including overdose with substances other than
opioids. Of increasing concern are more potent opioids and opioid combinations,
which may be less responsive to naloxone. These include carfentanil and U-
47700 (“gray death,” which includes a dangerous combination of fentanyl,
carfentanil, and heroin) (51,52). Along with the need to monitor patients for
continued naloxone requirements, another important consideration to anticipate
in administering naloxone is the possibility of initiating a significant withdrawal
syndrome.
Follow-Up Care
Pharmacological management of acute opioid overdose may be the first step in
engaging patients with opioid use disorders into medical care and addiction
treatment once the overdose event has resolved. In one study of 924 injection
drug users in Baltimore, MD, 368 (40%) reported ever having an overdose.
Twenty-six percent of the patients with an overdose sought drug treatment within
30 days after the event; the most common reason for seeking treatment was
noted to be speaking with someone about treatment options at the time of the
overdose. Multiple “missed opportunities” were noted: 87% of overdose patients
treated by emergency medical services, 74% of overdose patients treated in the
emergency room, and 57% of overdose patients hospitalized denied receiving
drug treatment information from the medical staff (53). Despite these and similar
findings, clinicians who manage overdose patients should establish the need for
ongoing addiction treatment as the major goal of patient management while
caring for overdose-related complications.
For medical personnel, two common questions that arise when patients with
opioid overdose are seen in the emergency department are which patients can be
discharged and when they can be discharged. Clearly, patients with major acute
medical or psychiatric comorbidities, including suicidal ideation, should be
hospitalized for further treatment. In the absence of these issues, resolution of
the symptoms of intoxication and establishment of follow-up referrals for
addiction, medical, and psychiatric care are necessary before a patient can be
discharged safely. In a study of 573 emergency department patients, a group of
investigators developed a clinical prediction rule to identify patients with opioid
overdose who could be safely discharged 1 hour after naloxone administration.
The authors reported that patients who can be safely discharged are those who
can mobilize as usual, have oxygen saturation on room air of >92%, have a
respiratory rate >10 breaths/min and <20 breaths/min, have a temperature of
>35.0°C and <37.5°C, have a heart rate >50 beats/min and <100 beats/min, and
have a Glasgow Coma Scale score of 15. Such patients are at lower risk of
adverse events (54). Models of emergency care that allow for initiation of
pharmacotherapy in the emergency department are more effective at engaging
patients in addiction treatment than brief intervention and referral. In a
randomized clinical trial of emergency department–initiated buprenorphine by
D’Onofrio et al., 78% of patients with opioid use disorder who presented to an
urban ED and were started on buprenorphine were engaged in addiction
treatment 30 days after the ED visit, compared with 37% in the referral group
and 45% in the brief intervention group (40).
Recent evidence suggests that naloxone also may have a role in the
prevention and treatment of opioid overdose when used in the community by
people who use drugs themselves. This concept is based on the fact that most
people who use illicit opiates have witnessed overdoses and many have
witnessed overdose-related deaths (55). Models of community-based naloxone
for overdose prevention have shown improvement in patient and bystander
recognition of overdose and use of naloxone (55,56). More importantly,
overdose education and naloxone distribution reduces death from heroin
overdose (54,57).
Other public health approaches aimed at reducing opioid overdose and
overdose mortality have shown promise in the literature. These include
community-based supervised injecting facilities (58–60) and use of
diacetylmorphine (ie, heroin) to treat heroin use disorder in countries where this
therapy is available (61,62).
OPIOID WITHDRAWAL
The opioid abstinence syndrome is characterized by two phases (63). In the
initial phase, patients with chronic opioid exposure experience acute withdrawal.
This is followed by the more chronic signs of a protracted abstinence syndrome.
Current pharmacotherapeutic strategies are based on this duality.
Acute Withdrawal
In the initial opioid withdrawal phase, the patient typically experiences a range
of symptoms, for varying lengths of time (depending on the half-life of the
opioid). Such symptoms include gastrointestinal distress (such as diarrhea and
vomiting), thermoregulation disturbances, insomnia, muscle and joint pain, and
marked anxiety and dysphoria. Although these symptoms generally (unless there
is acute medical comorbidity) include no life-threatening complications (unlike
alcohol withdrawal syndrome), the acute withdrawal syndrome causes marked
discomfort, often prompting continuation of opioid use even in the absence of
any opioid-associated euphoria.
Chronic Physiological Dependence and

Protracted Abstinence
In patients with a chronic opioid use disorder presenting with acute withdrawal,
medically supervised withdrawal or induction onto opioid agonist therapy is the
first step of treatment. Himmelsbach (14,63), reporting on 21 prisoners addicted
to morphine, observed that “physical recovery requires not <6 months of total
abstinence.” Factors he measured included temperature, sleep, respiration,
weight, basal metabolic rate, blood pressure, and hematocrit. The times required
for return to baseline ranged from 1 week to about 6 months. Martin and Jasinski
(64) reported in a subsequent study that this phase persisted for 6 months or
more after withdrawal and that it was associated with “altered physiological
function.” They found decreased blood pressure, decreased heart rate and body
temperature, miosis, and a decreased sensitivity of the respiratory center to
carbon dioxide, beginning about 6 weeks after withdrawal and persisting for 26
or more weeks. They also found increased sedimentation rates (which persisted
for months) and electroencephalogram changes.
Martin and Jasinski also postulated a relationship between the protracted
abstinence syndrome and relapse. Based on similar observations, Dole (65)
concluded that “human addicts almost always return to use narcotics” after
withdrawal in the hospital . In his article, he reviewed the relative importance of
metabolic and conditioned factors in relapse and concluded that the underlying
drive is metabolic, arguing that “psychological factors are only triggers for
relapse.”
The concept of protracted abstinence has been controversial (66), but
remains a useful model for scientific hypothesis testing and development of new
therapeutic approaches (67). Accordingly, Dole recommended methadone
maintenance treatment, even though “it does establish physical dependence.”
Because, as Dole pointed out, methadone continues physical dependence,
protracted abstinence may continue to be a problem whenever withdrawal
management from opioids is undertaken. However, methadone treatment, when
prescribed at appropriate doses, provides a “narcotic blockade,” which blocks
the euphoric effect of exogenous opioids and stabilizes psychosocial functioning
(68–71).
In addition to biological considerations, psychosocial concomitants of opioid
use disorder also necessitate longer, more specialized adjunct treatments for
these additional problems.
Clinical Picture
Withdrawal from opioids results in a specific constellation of symptoms.
Although some opioid withdrawal symptoms overlap withdrawal from sedative–
hypnotics, opioid withdrawal generally is considered less likely to produce
severe morbidity or mortality. Clinical phenomena associated with opioid
withdrawal include neurophysiological rebound in the organ systems on which
opioids have their primary actions (13). Thus, the generalized CNS suppression
that occurs with opioid use is replaced by CNS hyperactivity.
The severity of opioid withdrawal syndrome varies with the specific opioid
used and the dose and duration of drug use. In addition, route of administration
appears to be important as well. Data from one study suggests that injection drug
use is associated with significantly higher withdrawal symptom scores than was
inhaled opioid use for comparable heroin doses (72). The time to onset of opioid
withdrawal symptoms depends on the half-life of the drug being used. For
example, withdrawal may begin 4 to 6 hours after the last use of heroin, but up
to 36 hours after the last use of methadone.
Neuropharmacological studies of opioid withdrawal have supported the
clinical picture of CNS noradrenergic hyperactivity (73). Therapies to alter the
course of opioid withdrawal (such as clonidine) are designed to decrease this
hyperactivity, which occurs primarily at the locus coeruleus (74,75). Evidence
for the role of noradrenergic hyperactivity in opioid withdrawal has been
provided by studies showing elevated norepinephrine metabolite levels (76).
Diagnosis
The opioid withdrawal syndrome involves a constellation of clinical
manifestations. Several clinical tools are available to measure the severity of
opioid withdrawal. One such tool is the Clinical Opiate Withdrawal Scale
(COWS) (Table 53-3) (77). Other validated scales can also be employed for
assessment. These include the 10-item Short Opioid Withdrawal Scale, which
takes less than a minute to administer (78); the 16-item Subjective Opioid
Withdrawal Scale; and the 13-item Objective Opioid Withdrawal Scale (79).
Early findings may include abnormalities in vital signs, including tachycardia
and hypertension. Bothersome CNS system symptoms include restlessness,
irritability, and insomnia. Opioid craving also occurs in proportion to the severity
of physiological withdrawal symptoms. Pupillary dilation can be marked. A
variety of cutaneous and mucocutaneous symptoms (including lacrimation,
rhinorrhea, and piloerection—also known as “gooseflesh”) can occur as well.
Patients frequently report yawning and sneezing. Gastrointestinal symptoms,
which initially may be mild (anorexia), can progress in moderate to severe
withdrawal to include nausea, vomiting, and diarrhea. This combination of
uncomfortable symptomatology and intense craving frequently leads to return to
drug use (66).
TABLE 53-3 Clinical Opiate Withdrawal Scale

Adapted from “Flowsheet for measuring symptoms during buprenorphine induction.” Available at
www.naabt.org. Accessed November 1, 2007.
As with the onset of the opioid withdrawal syndrome, the duration also varies
with the half-life of the drug used and the duration of drug use. For example, the
meperidine abstinence syndrome may peak within 8 to 12 hours and last only 4
to 5 days (13), whereas heroin withdrawal symptoms generally peak within 36 to
72 hours and may last for 7 to 14 days (65).
A protracted abstinence syndrome has been described, in which a variety of
symptoms may last beyond the typical acute withdrawal period (80). Findings in
prolonged and protracted abstinence may include mild abnormalities in vital
signs and continued craving (81). Despite the extensive literature on protracted
withdrawal, a universal definition and diagnostic criteria are lacking, making
diagnosis difficult in individual patients (66).
Management
As in the management of opioid intoxication and overdose, management of
opioid withdrawal syndrome involves a combination of general supportive
measures and specific pharmacological therapies. It is very important for the
clinician to do a thorough evaluation to rule out other medical conditions that
may be complicating the opioid withdrawal syndrome. The choice of
pharmacotherapy used to treat withdrawal may be influenced by the presence
and severity of a patient’s underlying medical comorbidities (37).
In addition to assessment of general health, it is important to obtain objective
information to help guide the management of patients undergoing opioid
withdrawal. Thus, a physical examination should be performed to detect specific
findings consistent with withdrawal to establish the diagnosis.
General supportive measures for managing withdrawal include providing a
safe environment and adequate nutrition, as well as reassuring patients that their
symptoms will be taken seriously. Additionally, patients with underlying acute or
chronic pain need reassurance that their pain will be assessed and managed. The
decision as to whether to perform medically supervised withdrawal on an
outpatient or inpatient basis depends on the presence of comorbid medical and
psychiatric problems, the availability of social supports (such as family members
to provide monitoring and transportation), and the presence of use of multiple
drugs. Access to methods of medically supervised withdrawal also may affect
this decision; for example, methadone withdrawal management has been
restricted by federal legislation to inpatient settings or specialized licensed
outpatient drug treatment programs (82); however, more recent federal initiatives
allow some opioid-based treatments to be used under less restricted
circumstances (83,84).
In the course of managing the opioid withdrawal syndrome, clinicians also
need to be able to address medical conditions that commonly occur in people
with opioid use disorder (32,45). Issues such as acute bacterial infections, HIV,
and HCV-related consequences may complicate opioid withdrawal syndrome
presentation and management. For instance, some studies suggest diminished
expression of endogenous interferon-α and enhanced HCV viral replication in
patients both using and withdrawing from opioids suggesting that opioid use and
withdrawal favor HCV persistence in hepatocytes (85), whereas other studies
suggest that intravenous drug use increases cytokine response in patients
coinfected with HIV and HCV (86). In addition to recognition and management
of comorbid chronic viral infections, clinicians also need to be aware of
underlying acute and chronic pain as this can often complicate opioid use, opioid
craving, and opioid withdrawal. (See section 12 of this textbook (87).)
Pharmacological Therapies for Opioid
Withdrawal
Several pharmacological therapies are available to treat symptoms of opioid
withdrawal syndrome. These therapies involve the use of opioid agonists (such
as methadone), alpha-2 adrenergic agonists (such as clonidine), or an opioid
partial agonist (buprenorphine or buprenorphine/naloxone) (88).
Full Opioid Agonists

Slow Withdrawal from Methadone
It is important to distinguish between withdrawal from short-acting opioids such
as heroin (plasma half-life of morphine, the main metabolite: 3 to 4 hours) and
long-acting opioids such as methadone (plasma half-life: 13 to 47 hours). For
short-acting opioids, the natural course of the opioid withdrawal syndrome
generally is relatively brief, but more intense and associated with a higher degree
of discomfort than with equivalent doses of long-acting opioids. However, there
is considerable individual variation, so that strong early opioid withdrawal
symptoms from methadone are possible, as are delayed severe heroin withdrawal
symptoms.
One treatment strategy employing this general principle is to stabilize
patients with physiological dependence on heroin with methadone and then
gradually decrease the methadone dose over months rather than days. Initially,
methadone may be given in 5- to 10-mg increments, p.r.n., as the physical signs
of abstinence begin to appear, up to a total of 30 to 40 mg over the first 24 hours.
In the ambulatory setting, this treatment strategy can only be employed by
facilities licensed to prescribe methadone for the treatment of opioid use disorder
(89). In the acute hospital setting, methadone can be used to treat opioid
withdrawal without federal restriction. Ideally, patients are then transitioned to
outpatient methadone treatment at discharge.
The protocol for slow withdrawal from methadone is similar to the strategy
used for withdrawal from methadone maintenance treatment. After a stabilizing
dose has been reached, methadone can be tapered by 20% a day for inpatients,
leading to a 1- to 2-week procedure. Alternatively, the dose is tapered by 5% per
day for outpatients, in a gradual cessation phase lasting as long as 6 months (90).
Senay et al. (91) studied the effects of rapid (reductions of 10% of initial dose
per week) and gradual (3% per week) outpatient cessation under double-blind
conditions. They found that the 10% weekly decrements were associated with
higher dropout rates, increased illicit opioid use, and elevated levels of
subjective distress. The authors recommended a dose-tapering rate of about 3%
per week from methadone maintenance. On such a regimen, successful
withdrawal can be achieved by as many as 80% of inpatients and 40% of
outpatients, as measured by completion of withdrawal and a withdrawal-free
naloxone challenge test. The longer duration of the procedure and the greater
discomfort make outpatient withdrawal management with methadone especially
vulnerable to patient dropout and continuing illicit opioid use. One study showed
that even when coupled with enhanced psychosocial counseling, patients
enrolled in 6-month methadone withdrawal management programs demonstrated
greater illicit opioid use and greater drug-related HIV risk behaviors than
patients enrolled in methadone maintenance (92); therefore, methadone
withdrawal should only be employed in carefully selected patients.
Other Opioid Agonists

Medically supervised withdrawal from methadone maintenance treatment can be
especially challenging. Data from observational studies and randomized clinical
trials suggest that slow-release morphine is as effective as methadone in terms of
opioid withdrawal, opioid craving, or self-reported symptoms (93,94). However,
this approach should only be employed in highly monitored settings.
Alpha-2 Adrenergic Agents

Clonidine Withdrawal Management
Gold et al. (75) reported amelioration of opioid withdrawal symptoms by use of
clonidine and postulated that both morphine and clonidine blocked activation of
the locus coeruleus, a major noradrenergic nucleus that shows increased activity
during opioid withdrawal. Although opioids exert their effect through opiate
receptors, clonidine activates alpha-2 adrenergic receptors. Consequently,
clonidine does not possess the potential for creating the euphoria and
physiological dependence seen with opioids.
Trials of clonidine used to treat opioid withdrawal in the outpatient setting
also show some effect (95). Clonidine was reported to “reduce or eliminate most
of the commonly reported withdrawal symptoms,” including lacrimation,
rhinorrhea, restlessness, muscle pain, joint pain, and gastrointestinal symptoms.
However, symptoms such as lethargy and insomnia persisted. Sedation and
dizziness from orthostatic hypotension were reported as the most significant side
effects of clonidine. Though clonidine has been shown to be useful to decrease
symptoms associated with the opioid withdrawal syndrome, its use for this
purpose is considered off-label, and because it is not an opioid agonist, many
symptoms of opioid withdrawal remain untreated though they can be
ameliorated by a number of other adjunctive treatments (ie, nonsteroidal anti-
inflammatory drugs, bismuth subsalicylate, pharmacotherapy for insomnia,
dicyclomine).
For the treatment of opioid withdrawal, most protocols suggest 0.1 mg of
clonidine every 4 to 6 hours as needed for withdrawal discomfort on the first
day, followed by an increase in clonidine by 0.1 or 0.2 mg/d, to a maximum of
1.2 mg, with careful monitoring of blood pressure and withdrawal symptoms.
The average maximum dose is roughly 0.8 mg. Toward the end of the
withdrawal management period (days 5 to 7 in heroin withdrawal management),
the clonidine dose is tapered by 0.1 to 0.2 mg daily to avoid rebound
hypertension, headaches, and the reemergence of withdrawal symptoms. The
primary outcome for most research studies is achieving an opioid-free state in 10
days and undergoing a naloxone challenge without opioid withdrawal. In one
study, 80% of methadone-maintained patients (taking 5 to 40 mg/d) but only
36% of heroin-dependent patients were successfully detoxified using a clonidine
regimen (95).
Another study (96) confirmed the 80% completion rate for clonidine-assisted
methadone withdrawal management, but found that withdrawal symptoms of
anxiety, restlessness, insomnia, and muscle aches were the most resistant to
clonidine treatment. In an outpatient study comparing a slow methadone taper (at
1-mg decrements, beginning with a 20-mg daily methadone dose) with a
clonidine withdrawal management over 10 to 13 days, Kleber et al. (97)
demonstrated equal effectiveness, with 40% of subjects successfully completing
withdrawal management. In a 6-month follow-up, about one-third of the subjects
in each group had maintained abstinence. However, the authors noted that
clonidine offered some advantages for outpatient withdrawal management, in
that it poses minimal risk of diversion, is not a controlled substance and
therefore is more widely available to general physicians, and shortens the
withdrawal management period from 20 days (for the methadone taper) to 10 to
13 days (97).
Some reports suggest that clonidine does not induce euphoria (75), whereas
other reports suggest reinforcing properties associated with this drug in animals
(98). The reinforcing properties are relatively weak and are not morphine-like in
animals. Although there have been case reports of illicit use (99), this has not
become a widespread problem.
Lofexidine
Lofexidine, an analogue of clonidine that also is an agonist at the alpha-2
noradrenergic receptor, has shown promise as a withdrawal management agent.
It generally is reported to be as effective as clonidine (100,101) but more
economical and with fewer side effects. This medication is not available for use
in the United States.
Combined Clonidine and Naltrexone Treatment

Although clonidine alone improves symptoms of opioid withdrawal, it does not
alter the duration of the syndrome.. In one study, Kleber et al. found that addition
of the opioid antagonist naltrexone to clonidine shortened the duration of
withdrawal without increasing patient discomfort. However, the small naltrexone
doses used in this study were clinically impractical, because they were not
commercially available (102). Vining et al. (103) compared two rapid outpatient
opioid withdrawal management strategies (over 4 and 5 days), using clonidine
and naltrexone. In that study, the smallest naltrexone dose was 12.5 mg, or one-
quarter of a scored 50-mg naltrexone tablet. In the 4-day protocol, subjects
underwent a naloxone challenge test, followed by clonidine therapy administered
three times a day. The first naltrexone dose (12.5 mg) was given the afternoon of
the 1st day, after preloading with clonidine at 0.2 to 0.3 mg. Naltrexone was
increased to 25 mg on the 2nd day, 50 mg on the 3rd day, and 100 mg on the 4th
day. Clonidine was given at 0.1 to 0.3 mg three times per day, as needed, for the
first 3 days, and three times at 0.1 mg on the 4th day. The authors reported that
75% of patients successfully completed withdrawal management and were
discharged on maintenance doses of naltrexone. There was no difference in
withdrawal symptoms or severity between the 4- and 5-day protocols. Most
patients reported that withdrawal was “relatively comfortable.” Persistent
symptoms included anxiety, restlessness, insomnia, joint pain, and muscle aches.
Diazepam 10 mg twice a day on days 1 and 2 was found to be very effective for
persistent restlessness and muscle aches. In addition, clonidine lowered blood
pressure significantly, but resulted in no clinical problems. In summary, the
authors found that combined clonidine and naltrexone therapy had the advantage
of “being more rapid and probably more successful in the outpatient setting.”
The completion rate of 75% (compared with 40% for methadone or clonidine
alone) is another significant advantage. Finally, the initiation of naltrexone
during withdrawal eased the patients’ transition into naltrexone maintenance
treatment. Given the symptom intensity with this rapid method of withdrawal
management, it has been suggested that only clinicians with significant
experience in treatment of opioid withdrawal should offer this intervention.
Other protocols have suggested that the combination of very low-dose
naltrexone (0.125 to 0.25 mg/d) and low-dose clonidine ameliorated opioid
withdrawal symptoms better than either treatment alone (104).
Buprenorphine Withdrawal Management

Buprenorphine is a high-affinity, partial agonist at the mu opioid receptor.
Buprenorphine and buprenorphine/naloxone were approved by the U.S. Food
and Drug Administration in October 2002 as a pharmacotherapy for opioid
dependence (83,105,106). Additionally, the passage of the Drug Addiction and
Treatment Act of 2000 allowed physicians with advanced training to provide
treatment (ie, buprenorphine) for opioid dependence (DSM-IV) in an office-
based setting (83). Despite its higher unit dose cost compared with methadone,
buprenorphine has expanded access to opioid agonist treatment, reduced the
disparity between the number of opioid-dependent individuals and the number of
treatment slots available to them, and facilitated general medical care of
individuals with opioid use disorder (107,108).
Clinical research over the past 25 years has established that buprenorphine
(hereafter, this term includes both buprenorphine mono-products and
buprenorphine/naloxone combination products) is a safe and effective alternative
to methadone (109–117) and levomethadyl acetate hydrochloride (which was
removed from the European market and no longer manufactured in the United
States secondary to QT prolongation and fatal arrhythmias) (118) for opioid
agonist maintenance treatment. A recent Cochrane systematic review of 27
studies of over 3000 participants found that buprenorphine for opioid withdrawal
was superior to clonidine and lofexidine and as effective as methadone for
ameliorating withdrawal symptoms, treatment retention, and treatment
completion (119). It was also noted in this review that the duration of withdrawal
symptoms may be significantly less with buprenorphine compared with
methadone (119). These findings are highlighted in a multicenter randomized
clinical trial of a 13-day withdrawal management program using
buprenorphine/naloxone versus clonidine. In this study of 113 inpatients and 231
outpatients, 77% of inpatients receiving buprenorphine/naloxone versus 22% of
inpatients receiving clonidine and 29% of outpatients receiving
buprenorphine/naloxone versus 5% of outpatients receiving clonidine achieved
the study combined end point of treatment retention and opioid-free urine at
study completion (120). Follow-up analysis on this population found that
medication type was the single most important predictor of treatment completion
and treatment success regardless of treatment setting (121).
Treatment with buprenorphine also produces significant and substantial
improvements in psychosocial functioning over time (122). Buprenorphine also
has unique features that permit novel uses, which may alter current strategies for
maintenance and withdrawal management (105,123). In particular,
buprenorphine’s ceiling on agonist activity reduces the danger of overdose, may
limit its liability for misuse (124–126), and has low toxicity even at high
intravenous doses (127,128), thereby increasing the dose range over which it
may be administered safely.
Buprenorphine also can produce sufficient tolerance to block the effects of
exogenously administered opioids (125,129,130), suggesting that it reduces
illicit opioid use.
Buprenorphine’s slow dissociation from mu opioid receptors results in a long
duration of action (ideal for a maintenance medication) and also diminishes
withdrawal signs and symptoms on discontinuation, making it particularly useful
for the treatment of opioid withdrawal (131–136).
Literature suggests that buprenorphine is effective for the treatment of opioid
withdrawal. One study randomly assigned 45 patients with physical dependence
to heroin to buprenorphine (2 mg) or methadone (30 mg) for 3 weeks, followed
by a taper over a 4-week period, and found that the two approaches produced
equivalent results (110). Another study compared a gradual (36-day) with a more
rapid (12-day) buprenorphine taper (initially 8 mg) and found that the gradual
approach was superior (131). A pilot study comparing single-dose buprenorphine
of 32 mg to a 3-day buprenorphine withdrawal management found that these two
approaches were similar in terms of treatment completion (137). A study that
compared a 3-day course of buprenorphine (3 mg) to a 5-day course of clonidine
found these approaches were equivalent (133), although another study found that
a longer course of buprenorphine (13 days) was superior to clonidine (120). A
larger study (138) compared 162 patients physically dependent on heroin
detoxified in a primary care setting who were randomized to three 8-day
treatment protocols: clonidine, combined clonidine and naltrexone, and
buprenorphine. Participants in the combined clonidine and naltrexone group and
the buprenorphine group were more likely to complete withdrawal management
than the clonidine alone group, whereas the buprenorphine group experienced
less severe withdrawal symptoms than the other two groups.
Buprenorphine’s unique properties also make it a promising alternative to
methadone for use in special populations and treatment settings. Several studies
have shown buprenorphine to be safe and effective for the (139) treatment of
opioid use disorder among patients with HCV (139,140), HIV (141–143), and
HIV/HCV coinfection (144). The results of two retrospective cohort studies
found that using a short-term buprenorphine taper as a bridge to long-term
treatment facilitated treatment completion (145,146). Another study found that
initiating buprenorphine in an emergency department setting for the treatment of
opioid use disorder was more effective than brief intervention and referral at
engagement in addiction treatment (40).
In conclusion, buprenorphine is more effective than both clonidine and
lofexidine in reducing symptoms of withdrawal, retaining patients in treatment,
and allowing patients to reach treatment completion. Additionally, it is as
effective as methadone in tapering doses for the treatment of opioid withdrawal,
although withdrawal symptoms may resolve more quickly with buprenorphine
than with methadone. Gradual buprenorphine taper appears to be more effective
than rapid taper to treat opioid withdrawal. However, buprenorphine
maintenance remains superior to withdrawal management alone as a treatment
approach for opioid use disorder (147,148).
Rationale for Methadone-to-Buprenorphine Transfer

Some patients choose to transfer from methadone to buprenorphine for
maintenance or withdrawal management. This demand is driven by several
factors. First, there is the unique pharmacology of buprenorphine, leading to its
more favorable safety profile and longer duration of action relative to methadone
(123,149).
Second, buprenorphine may also be administered in office-based settings,
and patients may prefer this setting, rather than methadone treatment settings, for
their ongoing opioid agonist maintenance treatment (83). Third, because of its
enhanced safety, buprenorphine may be used effectively in clinical settings
outside opioid treatment programs (40,84,142,143,150,151).
Buprenorphine can produce withdrawal discomfort among volunteers with
physiological dependence on opioids under certain conditions (105). Low
buprenorphine doses may provide too little agonist effect (ie, insufficient relief
from withdrawal syndrome) relative to the maintenance opioid (methadone).
Alternatively, buprenorphine may directly precipitate withdrawal discomfort due
to its partial mu agonist properties leading to displacement of agonists. Among
individuals maintained on the long-acting, full mu opioid agonist methadone, the
high-affinity partial mu agonist buprenorphine is capable of abruptly reducing
the extent of mu opioid receptor stimulation. This would be expected to reduce
opioid agonist effects or precipitate withdrawal symptoms.
This principle has been amply demonstrated in humans: partial mu opioid
agonists such as nalorphine and butorphanol (152,153) can, in methadone-
maintained individuals, abruptly precipitate opioid withdrawal signs and
symptoms that are functionally similar to those produced by the antagonist
naloxone. Obviously, it would be ideal to avoid (or at least minimize)
precipitated withdrawal because this discomfort may translate into attrition and
relapse. Buprenorphine induction for patients who have been using short-acting
opioids (ie, heroin) should occur 6 to 12 hours after the last opioid use (105).
However, transferring patients from a longer-acting agonist such as methadone
to buprenorphine without producing significant withdrawal discomfort, attrition,
or relapse to drug use has been shown to be more challenging, as discussed in
the next section.
Studies Assessing Methadone-to-Buprenorphine Transfer

(Inpatient and Outpatient)
Several studies have attempted to address the issue of transitioning patients from
methadone to buprenorphine for treatment of opioid withdrawal. Several early
studies looked at the effect buprenorphine in methadone-maintained research
volunteers. Four programmatic studies examined the effect of time interval
between the last methadone maintenance dose and the initial buprenorphine dose
(152,154–156). Most participants in the four studies were maintained on
methadone 30 mg/d. When buprenorphine was administered to the volunteers,
buprenorphine significantly increased opioid withdrawal effects at 2 hours post
methadone (154) but not at 20 to 22 hours (152,154) or at 40 hours (156). Walsh
et al. systematically addressed whether methadone dose influences the response
to buprenorphine when 2, 4, or 8 mg of buprenorphine is administered
sublingually 40 hours after last methadone dose. Among individuals receiving
60 mg of methadone buprenorphine precipitated a dose-dependent increase in
opioid withdrawal symptoms. Whereas among individuals receiving 30 mg of
methadone, buprenorphine did not precipitate significant increases in opioid
withdrawal (156).
Several studies (154–156) have directly addressed whether buprenorphine
dose dependently precipitates opioid withdrawal in methadone-maintained
volunteers. Two studies (154,155) assessed whether buprenorphine (five active
doses from 0.5 to 8 mg intramuscularly) precipitated mild withdrawal at the 2-
hour interval. However, withdrawal severity was not dose related.
Several studies have directly examined a full medication transfer from
methadone to buprenorphine. Kosten and Kleber (157) reported an open-label
trial assessing full agonist to buprenorphine (sublingual liquid) transition. Eight
patients in this study were maintained on 25 mg/d of methadone and were
assigned to receive 2 mg (n = 4), 4 mg (n = 2), or 8 mg (n = 2) per day. Patients
were inducted onto buprenorphine within 24 hours after their last methadone
dose. The investigators reported that most patients completed the protocol, with
one dropping out due to persistent withdrawal and four reporting headache.
Seventy-eight percent of subjects had negative urine toxicology testing.
Withdrawal symptom ratings varied by buprenorphine dose, but were not dose
dependent.
In an open-label study, Banys et al. (158) examined the ability of sublingual
liquid buprenorphine to suppress opioid withdrawal 26 to 31 hours after
discontinuing methadone. Fifteen participants were allowed to take three low
doses of buprenorphine over several hours (0.15 mg at baseline, then 0.15 mg 1
hour later, and 0.3 mg 2 hours later) in an effort to relieve withdrawal signs and
symptoms. These low buprenorphine doses provided inadequate agonist effect to
offset methadone abstinence symptoms.
Lukas et al. (159) conducted the first double-blind, double-dummy pilot
study of three males—maintained on three different methadone doses (25, 58,
and 60 mg/d)—who were switched abruptly to buprenorphine 2 mg
subcutaneously. They found that buprenorphine did not fully substitute for
methadone during the transfer. Withdrawal signs and symptoms peaked within
the first several days of buprenorphine (depending on the measure) and abated
during buprenorphine stabilization.
Another published study of the methadone-to-buprenorphine (sublingual
liquid) full transfer is a within-subject, double-blind, double-dummy procedure
with inpatient volunteers (160). A moderate methadone maintenance dose (60
mg) was tapered over a few days (40 mg, 30 mg, 30 mg, and then 0 mg) before
initiating buprenorphine (4 mg on day 1, followed by 8 mg). Seventy-nine
percent (15 of 19) of participants who began the dose taper completed the
transfer. The 1-day methadone placebo (0 mg dose)—which produced a 48-hour
interval between the last active methadone dose and the first active
buprenorphine dose—significantly increased opioid withdrawal symptoms to a
“moderate” level. Peak withdrawal symptom scores occurred just before the first
buprenorphine dose. Opioid withdrawal symptoms remained elevated, but were
not significantly worsened, by the first two buprenorphine daily doses (4 mg,
then 8 mg). Withdrawal symptoms gradually were suppressed by subsequent
daily doses of buprenorphine (8 mg) and returned to baseline during
buprenorphine stabilization (8 mg/d). It is important to note that individuals were
given access to, and used, significant amounts of ancillary medications (mean
oxazepam dose of 45 mg/d and mean clonidine dose of 0.3 mg/d) to alleviate
withdrawal discomfort during the transfer period.
In a small double-blind, double-dummy pilot study (161), five male
outpatient volunteers with heroin use disorder were transferred from methadone
60 mg (with one intervening 45-mg dose) to the buprenorphine sublingual tablet.
On transfer day 1, buprenorphine significantly increased withdrawal symptoms
and decreased agonist symptoms and dose preference, as compared to
methadone stabilization. On buprenorphine transfer day 2, withdrawal symptoms
and blood pressure were elevated, but agonist symptoms and dose preference did
not significantly differ from methadone stabilization levels. Therefore, a 1-day
methadone dose taper to 45 mg was well tolerated relative to 60 mg/d
stabilization, and the transition from methadone 45 mg to buprenorphine 8-mg
tablet resulted in a time-related (throughout the same day) increase in opioid
withdrawal symptoms, which peaked during the evening (about 6 to 18 hours)
after the first buprenorphine 8-mg dose.
In another study conducted in Sydney, Australia, Breen et al. (162)
investigated the efficacy of three different transfer regimens from methadone to
buprenorphine: (a) among patients maintained on 30 to 40 mg of methadone
transfer at a fixed dose of 30 mg, (b) among patients maintained on 30 to 40 mg
of methadone transfer at a variable dose when uncomfortable, or (c) transfer at
entry dose provided entry dose of <30 mg. They found no difference in
withdrawal severity between the “transfer at a fixed-dose” group and the
“transfer when uncomfortable” group. Those patients that transferred on <30 mg
reported significantly less withdrawal discomfort.
Finally, Rosado et al. (163) showed that patients maintained on 100 mg of
methadone showed significant between-subject variability to the antagonistic
effects of buprenorphine when administered 24 hours after the last dose of
methadone among the 10 out of 16 patients completing the study.
These results suggest that it is feasible to transfer patients maintained on
methadone 30 to 60 mg/d to the buprenorphine 8 mg/d sublingual tablet,
although individualized refinements are needed to improve the tolerability and
clinical efficacy of this protocol. The data presented here imply that lower
methadone doses at the time of transfer and higher buprenorphine doses for
induction may be useful in suppressing residual withdrawal symptoms and
initiating illicit opioid abstinence in some individuals immediately after the
transfer and also may be preferred.
Buprenorphine in Agonist-to-Antagonist Treatment

Opioid antagonists represent an alternative to opioid agonist treatment for
patients with opioid use disorder. Opioid antagonists enhance relapse prevention
and also protect patients from opioid overdose given higher binding affinity than
opioid agonists. Transitioning from opioids to extended-release naltrexone can
be challenging. Buprenorphine has been used in several experimental studies
(110,157,164) as a transitional agent between agonists (such as methadone or
heroin) and antagonists (such as naloxone or naltrexone). In one study, Kosten
and Kleber (157) transitioned patients to buprenorphine at 2, 4, and 8 mg who
were either maintained on 20 to 30 mg of methadone or using heroin for 1 month
without precipitating substantial withdrawal symptoms. After chronic
administration, buprenorphine produces less physical dependence than do pure
agonists (ie, methadone), as suggested by the minimal withdrawal symptoms that
occur when buprenorphine is stopped and by the use of relatively higher mu
opioid antagonist doses that are needed to precipitate withdrawal in
buprenorphine-maintained volunteers (165). After 1 month of buprenorphine
stabilization, the medication was abruptly discontinued and a small dose of
naltrexone given 24 hours later. The investigators observed that the transition to
buprenorphine generally was well tolerated. The subsequent abrupt
discontinuation of buprenorphine was associated with “minimal withdrawal” in
the 2-mg and 4-mg buprenorphine groups, and a low dose of naltrexone (1 mg)
did not precipitate withdrawal. However, subjects in the 8-mg group reported a
more substantial increase in withdrawal symptoms when buprenorphine was
stopped.
Because of these properties, Kosten examined whether buprenorphine might
facilitate the transition from opioid agonists to antagonists in a three-step
process: (a) buprenorphine induction for individuals with maintained on agonists
such as methadone, (b) buprenorphine-induced reduction in physical
dependence, and (c) discontinuation of buprenorphine with rapid introduction of
naltrexone.
In a study testing that hypothesis, Kosten et al. (166) used intravenous
naloxone to challenge five patients with opioid use disorder who were
maintained on 3-mg sublingual buprenorphine. Induction onto naltrexone was
attempted in all of those patients who completed 30 days on buprenorphine. The
buprenorphine discontinuation and induction onto naltrexone included blinded
discontinuation of the buprenorphine, followed by double-blind, placebo-
controlled challenges with high-dose naloxone. Five male patients with opioid
use disorder who were maintained on buprenorphine 3 mg sublingually for 1
month as outpatients were abruptly discontinued from buprenorphine by blinded,
placebo substitution and enlisted in a placebo-controlled, double-blind challenge
with intravenous naloxone at 0.5 mg/kg. The naloxone was given over a 20-
minute period using a 10-mg/mL solution. Significant withdrawal symptoms
were precipitated. However, the severity of withdrawal was about two-thirds the
severity for patients maintained on methadone (Abstinence Rating Scale = 22;
SD = 9.3) and less than one-third of the full Abstinence Rating Scale score of 45.
Moreover, 5 hours after this naloxone challenge, withdrawal symptoms were at
baseline levels, and oral naltrexone was given at either 12.5 or 25 mg without
precipitating further withdrawal symptoms. The authors felt that the withdrawal
syndrome was milder for buprenorphine than for pure opioid agonists,
“suggesting a partial resetting of the opioid receptors by the antagonist activity
of buprenorphine.”
In some situations, combination treatment may facilitate greater patient
acceptance of agonist–antagonist switching. Thus, Gerra et al. (167) have shown
that the early use of naltrexone during withdrawal management in combination
with benzodiazepines and clonidine facilitated naltrexone acceptance by
patients. Umbricht et al. (168), in a study comparing buprenorphine taper alone
and buprenorphine with naltrexone, suggested that the combination treatment
may reduce the severity of withdrawal symptoms.
The use of buprenorphine stabilization of opioid withdrawal symptoms
before switching to naltrexone has the advantage of psychosocial stabilization
during withdrawal management. This approach thus may represent a
compromise between acute withdrawal management and long-term treatment of
chronic opioid use disorder for highly motivated patients who have significant
psychosocial support.
McCambridge et al. (169) published a cohort study with double-blind
allocation of treatment assignment of withdrawal management of inpatients with
physiological opioid dependence with either a 6-day withdrawal management
with lofexidine + naloxone, or lofexidine + placebo naloxone, or a 10-day
methadone taper. They found that lofexidine + naloxone was a superior
treatment strategy for patients who had not achieved opioid abstinence during
follow-up in terms of duration to first opioid use. Patients with long drug use
histories or using high doses of opioids, where transition to nonopioid treatments
may be uncomfortable, may require a combined protocol. This protocol would
place patients maintained on methadone or actively using heroin on
buprenorphine for several weeks, prior to transition to non-opioid
pharmacotherapy, to stabilize and engage them in the psychosocial aspects of
treatment. This could be followed by transition to naltrexone, using clonidine to
relieve any withdrawal symptoms caused by stopping the buprenorphine. Such
combination approaches are reviewed in an article by Stine and Kosten (170).
Sullivan et al. (171) performed a clinical trial looking at buprenorphine
versus naltrexone as a withdrawal management approach from opioid use to
induction onto extended-release naltrexone. One hundred and fifty treatment-
seeking adults were randomly assigned to one of two outpatient withdrawal
management regimens, naltrexone-assisted withdrawal management or
buprenorphine-assisted withdrawal management, followed by an injection of
extended-release naltrexone. The naltrexone withdrawal management arm lasted
7 days and included a single day of buprenorphine followed by ascending doses
of oral naltrexone along with clonidine and other adjunctive medications. The
buprenorphine withdrawal management arm included a 7-day buprenorphine
taper followed by a week-long delay before administration of extended-release
naltrexone. Participants from both groups received behavioral therapy focused
on medication adherence and a second dose of extended-release naltrexone.
Participants assigned to naltrexone withdrawal management arm were
significantly more likely to be successfully inducted to extended-release
naltrexone (56.1% compared with 32.7%) and to receive the second injection at
week 5 (50.0% compared with 26.9%) (171).
Other Agents
Agents other than opioid agonists and alpha-adrenergic agonists have been
investigated to treat the opioid withdrawal syndrome. Memantine compared to
buprenorphine in treatment of opioid withdrawal symptoms induced by
naltrexone was found to have comparable efficacy for objective signs but was
not superior to buprenorphine in terms of subjective symptoms (172). In one
study of 70 patients with opioid withdrawal, tramadol (600 mg/d) was found to
be as effective as methadone (60 mg/d) for objective opioid withdrawal (173).
Finally, investigations into the use of adjunctive gabapentin to ameliorate opioid
withdrawal symptoms occurring during methadone-assisted withdrawal found
that higher doses (1600 mg) may have some efficacy (174–176).
Role of Anesthesia-Assisted Ultrarapid Opioid

Withdrawal Management
There is a very limited role for this procedure as it is riskier and no more
successful than other methods (177,178).
Follow-Up Care
As with the management of opioid overdose, medical withdrawal management is
an important first step in the treatment of opioid use disorder. It must be made
clear that withdrawal management alone, without plans for ongoing treatment, is
not adequate to manage patients (37). Thus, at the initiation of withdrawal
management, arrangements for ongoing treatment need to be assured.
In general, withdrawal management programs focus solely on one aspect of
opioid use disorder (ie, treatment of withdrawal) and often lack appropriate
linkages to ongoing treatment services (179). Therefore, this approach to the
treatment of patients with opioid use disorder is not successful for most patients.
A systematic review of eleven studies looking at the addition of psychosocial
interventions to opioid agonist withdrawal management treatment found that
addition of psychosocial interventions improved treatment retention, abstinence
from opioids, and adherence to clinic visits (180). Opioid agonist treatment, on
the other hand, is effective for the ongoing treatment of patients with opioid use
disorder. Further research into withdrawal management–based treatments need
to take into account relapse prevention services.
CONCLUSIONS
The management of opioid intoxication and opioid withdrawal syndrome
requires that clinicians be familiar with the basic pharmacological properties of
opioids and the clinical manifestations of opioid overdose and withdrawal.
Specific pharmacotherapies and treatment models may be useful in the
management of opioid intoxication and opioid withdrawal syndrome. It is vital
for healthcare providers to be able to acutely recognize and manage severe
opioid intoxication and overdose. Management consists of acute supportive care
and administration of naloxone to reverse the opioid effect. Among patients with
opioid use disorder, an important consideration in the management of severe
intoxication and overdose is to link patients to ongoing care. Similarly,
recognition and management of opioid withdrawal are vital among providers
caring for patients in the inpatient or outpatient settings as withdrawal can lead
to ongoing opioid use and can seriously affect the management of other health
conditions. Acute withdrawal can be managed supportively and with
symptomatic treatment or with opioid agonist medications, which are generally
more successful at retaining patients in care. Protracted abstinence should be
addressed with a more systematic approach using a menu of options, which
includes opioid agonist treatment and/or counseling (withdrawal management
and counseling alone, however, are much less efficacious than opioid agonists).
Opioid agonist treatment has proven efficacy for the management of opioid
withdrawal and opioid use disorder. Healthcare provider education and
engagement in opioid intoxication, overdose and withdrawal recognition, and
treatment are critical to encourage further prevention and treatment of opioid
use, thereby impacting the public health opioid crisis.
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CHAPTER 54
Management of Stimulant,
Hallucinogen, Marijuana,
Phencyclidine, and Club Drug
Intoxication and Withdrawal
Jeffery N. Wilkins, Itai Danovitch, and David A. Gorelick
CHAPTER OUTLINE
Introduction
Stimulants
Hallucinogens
Marijuana
Dissociative Anesthetics
Inhalants
Club Drugs
MDMA (“Ecstasy”)
Gamma Hydroxybutyrate
Misuse of Herbs
Flunitrazepam
Serotonin Syndrome
Withdrawal from Multiple Drugs
Population-Specific Considerations
INTRODUCTION
This chapter reviews the treatment of acute intoxication and withdrawal states
associated with the use of stimulants such as cocaine and methamphetamine
(including their smokable forms, ie, “crack” and “ice”); hallucinogens such as
lysergic acid diethylamide (LSD); marijuana; dissociative anesthetics such as
phencyclidine (PCP), ketamine, and dextromethorphan (DXM); “club drugs”
such as 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) and
gamma-hydroxybutyrate (GHB); and commonly misused herbals. It also reviews
the treatment of the serotonin syndrome and withdrawal from multiple
substances. Psychiatric and medical complications are considered separately
because they often are treated differently and in different settings (eg, in
psychiatric vs. medical emergency departments). Not all of the substances
reviewed here have clinically distinct intoxication or withdrawal syndromes nor
are there pharmacological treatments for all such syndromes.
Successful treatment of acute intoxication, overdose, or withdrawal can
facilitate entry into addiction treatment by reducing uncomfortable withdrawal
symptoms that negatively reinforce taking an illicit substance. Even when
successful, these early stages of treatment often are followed by relapse to
substance use, with patients potentially reentering a “revolving door” of repeated
withdrawal management programs. Short-term treatment of acute intoxication or
withdrawal does not obviate the need for long-term treatment of addiction.
Pharmacological treatment of drug intoxication and overdose generally
follows one of the three approaches: increased clearance of drug from the body,
either by increasing catabolism or by increasing excretion, or both (1), blockade
of the neuronal site to which the drug binds to exert its effect (as through the use
of naloxone to block the mu-opioid receptor in the treatment of opiate overdose),
and counteracting effects of the drug through alternative neuropharmacological
action.
Pharmacological treatment of any drug withdrawal syndrome generally
follows one of the two approaches: suppression by a cross-tolerant medication
from the same pharmacological class—usually a longer-acting one to provide a
milder, controlled withdrawal (as in the use of the opioids methadone or
buprenorphine to treat opioid withdrawal syndrome)—and/or reducing the signs
and symptoms of withdrawal by targeting the neurochemical or receptor systems
that mediate withdrawal (as in the use of clonidine, a nonopioid medication, to
treat opioid withdrawal syndrome) (2).
The application of these pharmacological treatment approaches to the drugs
reviewed in this chapter is limited. There may be no practical method for altering
drug clearance (as with marijuana), or no specific drug receptor sites may have
been identified. Even when a receptor site has been identified, there may not be a
clinically useful antagonist. Finally, current understanding of the
neuropharmacological processes that mediate intoxication or withdrawal may be
too limited to suggest appropriate pharmacological interventions. Thus, clinical
stabilization, supportive management, and palliation of symptoms often remain
the mainstays of treatment.
STIMULANTS
Stimulant Intoxication
The acute psychological and medical effects of cocaine, amphetamines, and
other stimulants are attributable principally to increases in catecholamine
neurotransmitter activity. Enhanced catecholamine activity occurs through
blockade of the presynaptic neurotransmitter reuptake pumps (as by cocaine) and
by presynaptic release of catecholamines (as by amphetamines) (3). Resulting
stimulation of the corticomesolimbic dopamine brain reward circuit mediates the
desired (and addicting) psychological effects of stimulants. The resulting
stimulation of the sympathetic nervous system leads to peripheral
vasoconstriction (with organ ischemia), increased heart rate, and lowered seizure
threshold, among other adverse effects. Table 54-1 lists acute medical
complications of stimulant intoxication.
TABLE 54-1 Acute Medical Complications of Stimulant

Intoxication
aAll pulmonary complications except hyperventilation and pulmonary edema come primarily from the
smoked route of administration.
Sources: Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart. 2000;83:627-
633; Neiman J, Haapaniemi HM, Hillblom M. Neurological complications of drug abuse:
pathophysiological mechanisms. Eur J Neurol. 2000;7:595-606; Schuckit MA. Drug and Alcohol Abuse. A
Clinical Guide to Diagnosis and Treatment. 6th ed. New York: Springer, 2006; Tashkin DP. Airway effects
of marijuana, cocaine, and other inhaled illicit agents. Curr Opin Pulm Med. 2001;7:43-61. Refs. (4–7).
Blockade of presynaptic catecholamine reuptake sites or postsynaptic receptors

should, in principle, be an effective treatment for stimulant intoxication. Several
medications have attenuated the acute subjective effects of stimulants in phase I
human laboratory studies, such as bupropion (8), aripiprazole (9), risperidone
(10), topiramate (11), and modafinil (12), but none has been evaluated in a
realistic clinical setting.
Another method for treating stimulant intoxication might be to decrease drug
availability in the central nervous system (CNS) by binding it peripherally with
antidrug antibodies or by increasing its catabolism with catalytic antibodies or
with the endogenous cocaine-metabolizing enzyme butyrylcholinesterase
(BChE, E.C. 3.1.1.8) or other esterases (1). Treatment with a genetically
enhanced bacterial cocaine esterase (IV) (13) or BChE (conjugated to albumin:
sc) (14) significantly reduced the acute subjective and cardiovascular effects of
an IV cocaine challenge in phase I studies.
Table 54-2 gives an overview of treatment for the acute psychiatric and
medical complications of stimulant intoxication.
TABLE 54-2 Treatment of Acute Stimulant Intoxication

Psychological and Behavioral Effects of Stimulant
Intoxication
The initial effects of stimulant intoxication include increased energy, alertness,
and sociability, elation, euphoria, and decreased fatigue, need for sleep, and
appetite (15,16). At this stage, persons who use these stimulants often do not
seek or necessarily need treatment. With high dose or repeated use, stimulant
intoxication usually progresses to unwanted effects such as anxiety, irritability,
interpersonal sensitivity, hypervigilance, suspiciousness, grandiosity, impaired
judgment, stereotyped behavior, and psychotic symptoms such as paranoia and
hallucinations. Up to three-quarters of persons who use stimulants report
paranoia or psychotic symptoms associated with their use, although the
contribution of acute versus chronic stimulant exposure is often unclear (17).
These results may also reflect selection bias among these persons who come to
attention of clinicians. Persons who use stimulants typically remain alert and
oriented, but the delusional state may impair judgment, cognition, and attention.
Patients with stimulant-induced psychoses may closely resemble those with
acute schizophrenia and may be misdiagnosed as such (17). Cocaine-induced
psychosis may differ from acute schizophrenic psychosis in having less thought
disorder and bizarre delusions and fewer negative symptoms such as alogia and
inattention. Stimulant-induced hallucinations may be auditory, visual, or
somatosensory (17,18). Tactile hallucinations are especially typical of stimulant
psychosis, such as the sensation of something crawling under the skin
(formication). Specific genetic variations may account for some differences in
individual vulnerability to stimulant-induced psychosis (19). Panic reactions are
common and may evolve into a panic disorder (5). This may be exacerbated by
anxiety elicited by the physiological symptoms commonly associated with
stimulant use, such as palpitations and hyperventilation.
Very severe stimulant intoxication may produce an excited delirium or
organic brain syndrome that can be fatal (20). Such patients should be evaluated
promptly for an acute neurological lesion (eg, intracranial bleeding) or a
preexisting neuropsychiatric condition and be treated aggressively.
Management of Psychological and Behavioral Effects of

Stimulant Intoxication
The initial clinical evaluation should include a drug use history and drug
toxicology to confirm stimulant intoxication. As the patient’s condition permits,
further evaluation should rule out other potential medical (hyperthyroidism,
hypoglycemia) or neuropsychiatric (panic or bipolar affective disorder)
conditions (21). The initial treatment approach is nonpharmacological (22,23).
The patient should be observed in a quiet environment with minimal sensory
stimulation to avoid exacerbating symptoms. Treatment staff should interact in a
calm and confident manner, such as using the “ART” approach developed at the
Haight Ashbury Free Clinic in San Francisco: acceptance of the patient’s
immediate needs (such as pain relief or use of the bathroom) and reassurance
that the condition is due to the drug and likely will dissipate within a few hours
and “talk down” to provide reality orientation and avoid hostility. All procedures
should be explained to the patient before initiation. Physical restraints to control
agitation or violent behavior should be avoided unless absolutely necessary as
the use of restraints can increase the risk of hyperthermia and rhabdomyolysis,
with resulting severe medical complications (24).
If medication is needed, most experts prefer benzodiazepines (such as
diazepam [10-30 mg PO or 2-10 mg IM or IV] or lorazepam [2-4 mg PO or 1-2
IM or IV]) over antipsychotics to control severe agitation, anxiety, or psychotic
symptoms (5,25–27), although there are very few controlled clinical trials (25).
Benzodiazepines protect against the CNS and cardiovascular toxicities of
stimulants, whereas antipsychotics may worsen the sympathomimetic and
cardiovascular effects, lower the seizure threshold, increase the risk of
hyperthermia, or precipitate extrapyramidal reactions (26). Parenteral
benzodiazepine dosing may be repeated every 5-10 minutes until light sedation
is achieved. If an antipsychotic is needed to control psychosis, a high-potency
agent such as droperidol, haloperidol (5-10 mg PO, IM, or IV), or risperidone (2-
4 mg PO) is preferred because of its minimal anticholinergic activity.
Anticholinergic activity should be avoided because it may contribute to delirium
and hyperthermia (by impairing heat dissipation from sweating).
Chlorpromazine (28) and haloperidol (29) have been used safely in treating
children with severe amphetamine poisoning. There is little evidence to guide
treatment with second-generation antipsychotics, such as ziprasidone,
risperidone, quetiapine, and olanzapine. Aripiprazole has been suggested as a
promising medication because of its partial dopamine agonism (30).
A psychotic or agitated patient who has not responded to initial treatment
should be hospitalized until the episode has resolved. This usually occurs within
a few days if no more stimulants are ingested (5). Psychiatric symptoms that
persist beyond a few days suggest an etiology other than stimulant use
(22,31,32). Transient psychotic symptoms during periods of abstinence
(“flashbacks”) have been reported among persons who use methamphetamine
(33).
Medical Effects of Stimulant Intoxication

Mild stimulant intoxication (the state presumably desired by persons who use
stimulants) may be accompanied by one or more self-limiting physiological
effects such as restlessness, sinus tachycardia, hyperventilation, mydriasis,
bruxism, headache, diaphoresis, or tremor. These do not usually bring the
individual to medical attention or require treatment. Higher doses or repeated use
is associated with more serious medical events, including nausea and vomiting,
acute coronary syndrome (unstable angina or myocardial infarction, usually
resulting in chest pain), cardiac tachyarrhythmia, hypertension, seizures, stroke,
hyperthermia, or rhabdomyolysis (4,5,26,34–37). Acute medical complications
associated with acute stimulant intoxication are summarized in Table 54-1.
Stimulant use should be high on the list of possible diagnoses for any
younger patient presenting with one of these events, especially in the absence of
other risk factors (38,39). Urine or blood samples for toxicological analysis
should be obtained to determine what drugs, if any, the patient has ingested
recently. Even if an apparently adequate history has been obtained, the patient or
their collateral informants may not know the true content of any street drugs that
have been used. Stimulant use within the preceding 96 hours or a positive
toxicology test is highly suggestive. The actual blood cocaine concentration has
little prognostic significance (40).
Nontraumatic chest pain is a common presenting complaint among persons
who use stimulants who seek acute medical care. The differential diagnosis
includes acute coronary syndrome, acute aortic dissection, pneumothorax or
pneumomediastinum (especially in those who have smoked the drug),
endocarditis or pneumonia (especially among people who inject drugs),
pulmonary embolus, myocarditis or cardiomyopathy, or musculoskeletal pain
after a seizure (26,37). About 1%-6% of patients with cocaine-associated chest
pain and up to one-fourth of those with methamphetamine-associated chest pain
will have an acute myocardial infarction (26,41). The risk for infarction is
greatest during the first 1-3 hours after cocaine use and then declines rapidly
(41). Concurrent use of multiple stimulants (eg, cocaine and methamphetamine)
or of cocaine and alcohol (which produces cocaethylene) may enhance
cardiotoxicity (16), whereas concurrent use of opioids (such as “speedballing”)
may mask the diagnosis (42).
The electrocardiogram is not always helpful diagnostically because of its
low sensitivity and positive predictive value and the high frequency (more than
one-third in some studies) of benign early repolarization among patients
presenting with cocaine-associated chest pain (43,44). The best laboratory test
for acute myocardial infarction is serial blood levels of cardiac troponin I
(38,41). Its high specificity (around 95%) for acute myocardial infarction is not
affected by recent cocaine use because it does not cross-react with skeletal
muscle troponin. In contrast, myoglobin and creatine kinase (CK) levels may be
elevated due to cocaine-associated rhabdomyolysis.
Patients who present with nontraumatic stimulant-associated chest pain
usually should be observed for 9-12 hours while undergoing evaluation (45).
Delayed complications are rare, so resolution of symptoms with a negative
evaluation warrants discharge. Patients who have persistent chest pain despite
standard treatment, hypotension, congestive heart failure, or cardiac arrhythmia
require hospitalization for further evaluation and treatment. Even patients with
confirmed acute myocardial infarction have a favorable prognosis, possibly
because of their relatively young age and good underlying health (41).
Rhabdomyolysis may be due to a direct effect of the drug, hyperthermia,
excessive muscle activity, or trauma (24). The usual symptoms of myalgia and
muscle tenderness and swelling often are absent in rhabdomyolysis associated
with stimulants. The diagnosis is suggested by a plasma CK level greater than
five times normal (with other tissue sources such as brain and cardiac ruled out)
and a urine dipstick positive for heme, the nonprotein component of hemoglobin,
but without red blood cells (indicating free myoglobin [or hemoglobin] in the
urine).
Management of Medical Effects of Stimulant Intoxication

The first priority in the management of severe acute stimulant intoxication is
maintenance of basic life-support functions (27). Vital signs, hydration status,
and neurological status should be monitored closely. Activated charcoal or
gastric lavage with isotonic saline may be helpful if a large amount of stimulant
has been taken orally within the preceding hour (5,23). This can be done by oral
intake or via a nasogastric tube in the awake, cooperative patient. Activated
charcoal (50-100 g orally) may be just as effective as gastric lavage and
minimizes the risk of aspiration. Ipecac-induced vomiting is not recommended.
Severe hypertension (eg, diastolic blood pressure >120) that lasts more than
15 minutes should be treated promptly to avoid CNS hemorrhage (5).
Rhabdomyolysis should be treated vigorously with intravenous fluid to maintain
a urine output of >2 mL/kg/h to avoid myoglobinuric renal failure (5,23).
Maintenance of urine pH > 5.6 with sodium bicarbonate (1 mmol/kg IV) helps to
prevent the dissociation and precipitation of myoglobin.
Benzodiazepines in sedative doses are the initial treatment of choice for both
acute cardiovascular and CNS toxicity from stimulants (38,43). Hypertension or
tachycardia that does not respond to sedation alone may be treated with an
alpha-adrenergic blocker such as phentolamine (2-10 mg IV over 10 minutes).
Beta-adrenergic blockers such as propranolol or esmolol should be used with
caution because of the risk of unopposed alpha-adrenergic stimulation by the
stimulant, resulting in vasoconstriction and worsening hypertension
(38,41,44,46). The combined alpha- and beta-adrenergic blocker labetalol shows
little alpha-adrenergic antagonism in clinical practice; its use should be avoided.
However, despite concerns about the use of beta-blockers, at least one study has
not found them to be associated with worse outcomes (47). If alpha-adrenergic
blockade is ineffective, direct vasodilation with sodium nitroprusside infusion
(0.25-10 μg/kg/min) or nitroglycerin (5-100 μg IV) can be used. There is no
evidence that rapid lowering of blood pressure compromises peripheral
(including cerebral) circulation in an otherwise intact patient. Calcium channel
blockers may reduce vasospasm, but their role remains unclear; calcium channel
blockers enhance CNS toxicity in animal studies, have inconsistent effects in
case series, and should be avoided in patients with heart block or heart failure.
Dexmedetomidine, an α2-adrenergic receptor agonist, has shown promise in
ameliorating the acute cardiovascular effects of severe cocaine intoxication, as
well as providing sedation (48,49). It must be given by IV infusion (not bolus) to
avoid hypertension and bradycardia.
Treatment of cocaine-induced cardiac tachyarrhythmias begins with
correction of any exacerbating conditions such as myocardial ischemia, hypoxia,
electrolyte abnormalities, or acid–base disturbance (41,45). Arrhythmias
occurring several hours after cocaine use are usually secondary to myocardial
ischemia. Standard arrhythmia management is usually appropriate, including use
of lidocaine. Arrhythmias occurring immediately after cocaine use are usually
from the sodium channel blocking action of cocaine. These may respond to
sodium bicarbonate. Lidocaine (which also blocks sodium channels) should be
used cautiously in this context because of animal studies suggesting it
exacerbates cocaine-associated arrhythmias and seizures. Class IA
antiarrhythmic medications (such as quinidine, procainamide, or disopyramide)
should be avoided because of their potential additive effect on QRS and QT
interval prolongation. There are no data on the use of amiodarone for cocaine-
associated arrhythmias. Treatment of cardiac arrest is the same as for those who
do not use cocaine; the outcome may be more favorable than for drug-free
patients (50).
The treatment of stimulant-associated acute coronary syndrome largely
resembles that for the non–drug-associated syndrome, with the exception of
avoiding use of beta-adrenergic blockers and labetalol (45,46). Initial treatment
includes oxygen, benzodiazepine for sedation, morphine for pain, sublingual
nitroglycerin for vasodilation, and aspirin for antiplatelet action, while
evaluation is continuing. Further treatment can include phentolamine or
intravenous nitrates (10 μg/kg/min) to lower blood pressure and reverse coronary
artery vasoconstriction. The role of calcium channel blockers is not well-defined
(38,41). They may be useful in patients who have not responded to
benzodiazepines and nitroglycerin.
Both fibrinolytic therapy and percutaneous transluminal coronary
angioplasty have a role in the treatment of confirmed myocardial infarction
(38,41). Angioplasty may be preferable to fibrinolysis because of the increased
risk of intracranial hemorrhage in persons who use cocaine. Elevated body
temperature (>102°F orally) is a marker for poor prognosis and should be
managed aggressively to avert hyperthermic crisis (as by cold water sponging,
cooling blankets, ice packs, ice water gastric lavage, or cold peritoneal lavage)
(5,51). Untreated hyperthermia may result in rhabdomyolysis and renal failure.
Intravenous benzodiazepines (diazepam 5-10 mg or lorazepam 2-10 mg over
2 minutes, repeated as needed) are recommended to control seizures stemming
from stimulant intoxication (48,51). Fosphenytoin (15-20 mg/kg at 100-150
mg/min) or phenobarbital (15-20 mg/kg over 20 minutes) also can be used.
However, the latter may cause hypotension or prolonged sedation.
Excretion of amphetamine can be increased by acidifying the urine to pH <
6.6 (as with 500 mg of oral ammonium chloride every 3-4 hours), which inhibits
renal reabsorption of amphetamine (52). The actual clinical usefulness of this
maneuver is uncertain (16). Acidification is contraindicated in the presence of
myoglobinuria, if renal or hepatic function is abnormal, or in overdose
situations, when plasma acidification may compromise cardiovascular function
(31).
Stimulant Withdrawal
Abrupt cessation of stimulant use is associated with depression, anxiety, fatigue,
difficulty concentrating, anergia, anhedonia, increased drug craving, increased
appetite, hypersomnolence, and increased dreaming (because of increased REM
sleep) (53–55). The initial period of intense symptoms is commonly termed the
“crash,” but most symptoms are mild and self-limited, resolving within 1-2
weeks without treatment.
Hospitalization for stimulant withdrawal is rarely indicated on medical
grounds and has not been shown to improve the short-term outcome for
stimulant addiction (56,57). Pharmacological treatment has focused more on
long-term treatment of addiction than on short-term treatment of acute
withdrawal (58,59). Most clinical trials that used medication during the early
withdrawal period have continued to use such medication for at least several
weeks, with the additional goal of treating the addiction itself.
Medical Effects of Stimulant Withdrawal

The 1st week of stimulant withdrawal has been associated with myocardial
ischemia (60), possibly because of coronary vasospasm. Other medical effects of
stimulant withdrawal are relatively minor, including nonspecific musculoskeletal
pain, tremors, chills, and involuntary motor movement (61). These rarely require
specific medical treatment.
Management of Stimulant Withdrawal

The stimulant withdrawal syndrome has been hypothesized to be the result of
decreased levels of brain dopamine activity resulting from chronic stimulant
exposure. This so-called “dopamine deficiency” hypothesis of withdrawal has
not been consistently supported by clinical studies (62–64) but has generated the
use of dopamine agonists to treat cocaine withdrawal, most commonly
bromocriptine and amantadine. However, no medication has been shown to be
consistently effective in controlled clinical trials (65) or is any medication
approved for the treatment of stimulant withdrawal by any national regulatory
authority. Administration of a cross-tolerant or similarly acting stimulant has not
been systematically evaluated as a short-term treatment for stimulant withdrawal
(22). No controlled clinical trial has directly compared the benefits of medication
versus a supportive milieu. Two small controlled clinical trials found modafinil
(100-200 mg daily over 7 days) not different from placebo (66) and electrical or
auricular acupuncture (thrice weekly over 4 weeks) significantly more effective
than no treatment (there was no sham control) (67).
Symptoms of stimulant withdrawal are best treated supportively with rest,
exercise, and a healthy diet (5,22). Short-acting benzodiazepines such as
lorazepam may be helpful in selected patients who develop agitation or sleep
disturbance. Severe (suicidal ideation) or persistent (>2-3 weeks) depression
may require antidepressant treatment (5) and psychiatric admission. The risk of
relapse is high during the early withdrawal period, in part because drug craving
is easily triggered by encounters with drug-associated stimuli. This issue is better
addressed by psychosocial treatment, such as supportive therapy, cognitive–
behavioral therapy, relapse prevention, and contingency management, rather than
by medication.
HALLUCINOGENS
Hallucinogen Intoxication
Hallucinogens have in common the ability to change or distort sensory
perceptions in a clear sensorium. Most hallucinogens fall into one of two
chemical groups (see Chapter 14). Indolealkylamine hallucinogens (including
LSD, psilocybin, or N,N-dimethyltryptamine) are structurally related to
serotonin; phenylethylamine hallucinogens (including 3,4,5-
trimethoxyphenethylamine [mescaline], 3,5-dimethoxy-4-methylamphetamine
[DOM, STP]) are structurally related to norepinephrine (68–70). Both
indolealkylamine and phenylethylamine hallucinogens generate psychedelic
(LSD-like) experiences and thus are often categorized together. In contrast, 3,4-
methylenedioxymethamphetamine (MDMA, “ecstasy”) has characteristics of
both a hallucinogen and a stimulant and is considered separately (see also
Chapter 14). PCP and its close analog ketamine are anesthetics that are used for
their dissociative and euphoric effects. Both MDMA and PCP are considered in
their own section below (see also Chapter 15).
Psychological and Behavioral Effects of Hallucinogen

Intoxication
The acute psychological and behavioral effects of hallucinogen intoxication are
summarized in Table 54-3. The subjective experience is influenced greatly by set
and setting, that is, the expectations and personality of the person who uses
hallucinogens, coupled with the environmental and social conditions of use.
Mood can vary from euphoria and feelings of spiritual insight to depression,
anxiety, and terror (71,72). Perception usually is intensified and distorted, with
alterations in the sense of time, space, and body boundaries. While illusions
(visual and auditory distortions of perception) are common, true hallucinations
(perceptions that do not have any basis in reality) are not. Synesthesia, a
blending of the senses wherein colors are heard and sounds are seen, is a
common perceptual distortion. Cognitive function may range from clarity to
confusion and disorientation, although reality testing usually remains intact.
Acute LSD intoxication may last up to 12 hours, with little evidence of acute
tolerance (73).
TABLE 54-3 Acute Psychological and Behavioral

Effects of Intoxication With LSD, Marijuana, PCP, or
MDMA
Relative weighting: X = mild; XX = moderate; XXX = marked; /= common/rare; ? = insufficient research.
MDMA, 3,4-methylenedioxymethamphetamine.
Sources: Brust, JCM. Neurologic complications of illicit drug abuse. Continuum (Minneap Minn).
2014;20:642-656; Frecska E, Luna LE. The adverse effects of hallucinogens from intramural perspective.
Neuropsychopharmacol Hung. 2006;8:189-200; Abraham HD, Aldridge AM, Gogia P. The
psychopharmacology of hallucinogens. Neuropsychopharmacology. 1996;14:285-298. Refs. (69–71).
A “bad trip” usually takes the form of an anxiety attack or panic reaction, with
the person feeling out of control (71). An experience of depersonalization may
precipitate the fear of losing one’s mind permanently. Panic reactions are more
common in those who have limited experience with hallucinogens, but previous
“positive” experiences provide no protection against an adverse reaction (74).
While higher doses are associated with more intense experiences, adverse
reactions are less a function of dose than of context and environment.
Hallucinogens may trigger a transient psychosis even in persons who are
psychologically normal; however, a true psychotic episode is rare. Hallucinogen-
induced psychosis may resemble acute paranoid schizophrenia. The two usually
can be distinguished because patients with schizophrenia tend to have auditory
(rather than visual) hallucinations and a history of prior mental illness. Persons
who use hallucinogens, unlike patients with schizophrenia, usually retain at least
partial insight that their symptoms are drug related. However, hallucinogen use
can trigger or exacerbate psychotic disorders or result in persisting or delayed
symptoms (73,74). The specific risk factors for these adverse outcomes are
poorly understood.
Hallucinogen ingestion may result in an acute toxic delirium that is
characterized by delusions, hallucinations, agitation, confusion, paranoia, and
inadvertent suicide attempts (eg, attempts to fly or perform other impossible
activities).
Medical Effects of Hallucinogen Intoxication
Acute medical complications of hallucinogen intoxication are summarized in
Table 54-4. Sympathomimetic effects are common, particularly pupillary
dilation, hyperreflexia, piloerection, tachycardia, and increases in blood
pressure. Dizziness, paresthesias, headache, nausea, or tremor may occur. Body
temperature should be monitored and any elevation treated promptly (75). Dry
skin, increased muscle tone, agitation, and seizures are warning signs of a
potential hyperthermic crisis. Patients may not respond to anticonvulsant
medication until body temperature is lowered. Complications that require
treatment are rare in the absence of overdose (76,77).
TABLE 54-4 Acute Medical Complications of

Intoxication with LSD, MDMA, Marijuana, or PCP
MDMA, 3,4-methylenedioxymethamphetamine; HR, heart rate; BP, blood pressure.

Sources: Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart. 2000;83:627-
633; Brust JCM. Neurologic complications of illicit drug abuse. Continuum (Minneap Minn).
2014;20:642-656; Frecska E, Luna LE. The adverse effects of hallucinogens from intramural perspective.
Neuropsychopharmacol Hung. 2006;8:189-200; Kalant H. The pharmacology and toxicology of “ecstasy”
(MDMA) and related drugs. Can Med Assoc J. 2001;165(7):917-928; Schuckit MA. Drug and alcohol
abuse. A Clinical Guide to Diagnosis and Treatment. 6th ed. New York: Springer, 2006; Selden BS, Clark
RF, Curry SC. Marijuana. Emerg Med Clin North Am. 1990;8:527-539. See Refs. (75,76).
Oral LSD is rapidly absorbed, so that ipecac-induced vomiting or gastric lavage

usually is not helpful and may exacerbate the patient’s psychological distress.
There is no evidence that LSD binds to charcoal. Gastric lavage may be useful in
psilocybin ingestion or when there is doubt as to the identity of the ingested
mushrooms (78).
Management of Hallucinogen Intoxication

Initial treatment is supportive. The patient should be placed in a quiet
environment with minimal sensory stimulation but should be observed because
of the risk of unintended self-injury (as the result of delusions or hallucinations)
or of suicide (as the result of depression). The presence of a familiar person
usually is comforting. Unless the patient presents in an acutely agitated or
threatening state, physical restraints are contraindicated because they may
exacerbate anxiety and increase the risk of rhabdomyolysis associated with
muscle rigidity or spasms. The use of “gentle restraints” in combination with
muscle massage and individualized counseling may be helpful (77).
The “talk down” or reassurance technique may be helpful. The clinician, in a
concerned and nonjudgmental manner, discusses the patient’s anxiety reaction,
stressing that the drug’s effects are temporary and that the patient will recover
completely.
For patients who do not respond to reassurance alone, oral benzodiazepines
such as lorazepam (1-2 mg) or diazepam (10-30 mg) are the drugs of choice
(68). When oral medication is too slow, or the patient will not take oral
medication, intramuscular lorazepam (2 mg, repeated hourly as needed) may be
effective. If benzodiazepines are insufficient, a high-potency antipsychotic such
as haloperidol (0.25-10 mg per dose) may be needed. The role of second-
generation antipsychotics in this situation remains unclear, but 5-HT2A receptor
antagonism may be a useful property (68–70). Phenothiazines should be avoided
because they are associated with poor outcomes (77) and may exacerbate
unsuspected anticholinergic poisoning.
Patients usually recover sufficiently after several hours and may be released
into the care of a responsible relative or friend. If psychosis does not resolve
within 1 or 2 days, ingestion of a longer-acting drug such as PCP or DOM
should be suspected. Symptoms that persist beyond a few days raise the strong
likelihood of a preexisting or concurrent psychiatric or neurological condition.
Psychiatric problems that last more than a month probably are related to
preexisting psychopathology.
Treatment for hallucinogen-induced delirium generally follows the
guidelines for simple intoxication: isolate the patient, and minimize sensory
input until effects of the drug have worn off. Reassurance that the delirium will
abate as the drug is metabolized also may be helpful. Pharmacological treatment
is not necessary in most cases and may confuse the clinical picture. If medication
is needed, neuroleptic agents such as haloperidol (0.25-10 mg per dose),
risperidone (0.25-4 mg per dose), or olanzapine (1.25-20 mg per dose) may be
useful in attenuating agitation.
Hallucinogen Withdrawal
Withdrawal symptoms, including fatigue, irritability, and anhedonia, are reported
by about 10% of persons who use hallucinogens (76). There is no evidence to
suggest a clinically significant hallucinogen withdrawal syndrome (68,79), and
such a syndrome is not recognized in the DSM-5 (80). The rapid development of
tolerance (within 3-4 days) may explain in part why use of LSD-like drugs
generally is intermittent. There is no role for medication in the treatment of
hallucinogen withdrawal.
Some persons who use hallucinogens describe experiencing flashbacks,
vivid memories, or brief recurrences of sensory distortions reminiscent of
intoxication, during periods of sobriety. Flashbacks can occur spontaneously
long after cessation of use and thus are not truly a withdrawal syndrome. In the
American Psychiatric Association’s Diagnostic and Statistical Manual of Mental
Disorders, 5th ed. (DSM-5), these patients are diagnosed as “hallucinogen
persisting perception disorder” (73,74). Initiation of selective serotonin reuptake
inhibitors (SSRIs) or neuroleptics is associated with recurrences of flashbacks in
at-risk individuals (73,81). Supportive measures, as well as the symptom-based
pharmacological interventions prescribed to manage hallucinogen intoxication,
may be effective in managing such symptoms.
MARIJUANA
Marijuana Intoxication
The major psychological and physiological effects of marijuana are mediated by
the interaction of delta-9-tetrahydrocannabinol (THC) , the primary psychoactive
compound in the Cannabis plant (82) with specific cannabinoid (CB1) receptors
on nerve cells (83–85), the regional distribution of which in the human brain is
consistent with the known effects of marijuana. Other cannabinoids found in
marijuana (eg, cannabidiol, cannabinol) do not produce these typical marijuana
effects (82). In animal and human studies, acute THC effects are reduced or
blocked by CB1 receptor antagonists (86).
Psychological and Behavioral Effects of Marijuana

Intoxication
The initial—usually desired—psychological effects of marijuana intoxication
include relaxation, euphoria, slowed time perception, altered (often intensified)
sensory perception, increased awareness of the environment, and increased
appetite (87). Undesired effects may include impaired concentration, anterograde
amnesia, and motor incoordination (87,88). As with hallucinogens,
psychological set and social setting and prior experience with the drug can
substantially influence the quality of the experience. Higher doses, repeated use,
or a stressful setting is associated with adverse effects such as hypervigilance,
anxiety, paranoia, derealization and depersonalization (commonly associated
with altered time sense), acute panic (associated with anxiety), illusions or
hallucinations (usually auditory or visual), psychosis, or delirium (87,88). Acute
marijuana-associated psychosis can be difficult to distinguish from
schizophrenic psychosis other than by its transient time course (89). Marijuana-
associated psychosis may be more likely to exhibit
derealization/depersonalization experiences and visual, rather than auditory,
hallucinations (90). Preexisting psychopathology increases the risk of adverse
events such as panic attack or psychosis (94). Table 54-3 summarizes the acute
adverse psychological effects of marijuana intoxication. Oral ingestion of
marijuana can produce the same adverse reactions as does smoking, including
psychosis (91–94).
Medical Effects of Marijuana Intoxication

The acute physiological effects of oral or smoked marijuana intoxication include
conjunctival injection (“red eye”) due to vasodilation, tachycardia (sometimes
with palpitations), orthostatic hypotension (sometimes resulting in syncope), and
dry mouth (see Table 54-4). Neurological signs include poor motor coordination,
head jerks, and impairment of smooth pursuit eye movements (95). These
generally are mild, are self-limiting, and do not require medical treatment. There
are no well-established cases of human fatalities from exclusive marijuana
overdose (88), although one prospective case series found an association
between recent marijuana use and myocardial infarction and an increased risk of
subsequent death (96). Marijuana smoking has been associated with atrial
fibrillation (97,98). Intravenous use of marijuana, although rare, can be
associated with cardiovascular shock and renal failure (99).
Management of Marijuana Intoxication

Adverse effects of marijuana intoxication tend to be self-limited and often can be
managed without medication. The patient should be kept in a quiet environment
and offered supportive reassurance. If immediate pharmacological intervention is
needed to control severe agitation or anxiety, benzodiazepines are preferred to
antipsychotics, although there are no controlled studies to confirm this.
Psychosis usually responds to low doses of second-generation antipsychotics.
No medication is approved by the U.S. FDA (or any other national
regulatory authority) for the treatment of marijuana intoxication (100). The
selective cannabinoid CB1 receptor antagonist/inverse agonist rimonabant
(developed for weight loss) blocked the acute psychological and cardiovascular
effects of smoked marijuana in human laboratory studies (86). However,
rimonabant and several similar medications were withdrawn from the market
and from clinical development in 2008 because of psychiatric side effects. Small
clinical trials suggest that propranolol (120 mg orally) may reduce some of the
subjective and cardiovascular effects of acute marijuana intoxication (101) and
that both first- and second-generation antipsychotics are effective in relieving
marijuana-induced psychosis (102,103).
Marijuana Withdrawal
Acute marijuana withdrawal is reported by up to one-third of those with heavy
marijuana use in the community and more than half of those seeking treatment
for marijuana (DSM IV) dependence (104) and is a recognized clinical
syndrome in DSM-5 (80). Symptoms are primarily psychological, including
irritability, anxiety, depression, restlessness, anorexia, insomnia, and disturbed
sleep (105). Much less common are physical symptoms such as gastrointestinal
distress, diaphoresis, chills, nausea, shakiness, muscle twitches, and increased
blood pressure (106). The syndrome is usually mild, comparable to tobacco
withdrawal (107), and rarely needs medical attention but may impair some
normal activities of daily life. It may warrant clinical attention in the treatment
of cannabis use disorders because withdrawal symptoms can serve as negative
reinforcement for relapse among those trying to maintain abstinence (105).
Management of Marijuana Withdrawal

Marijuana withdrawal rarely requires treatment for intrinsic medical or
psychiatric reasons, although treatment might be warranted in some cases to
reduce the risk of relapse in persons trying to abstain while experiencing
distressing withdrawal symptoms. No medication is approved by the U.S. FDA
(or any national regulatory authority) for the treatment of marijuana withdrawal
(100). In controlled clinical trials involving treatment-seeking adults with
moderate–severe cannabis use disorder, dronabinol (oral synthetic THC, 30, 40,
or 60 mg daily) (109,110), gabapentin (1200 mg daily in divided doses) (108),
and nabiximols (1:1 mixture of THC + cannabidiol as a sublingual spray, not
available in the United States) (111) significantly reduced marijuana withdrawal
symptoms, although only gabapentin significantly reduced marijuana use. For
sleep disturbance associated with marijuana withdrawal, small clinical trials
suggest that zolpidem (12.5 mg extended release at bedtime) or nitrazepam (10
mg at bedtime) may be helpful (100).
DISSOCIATIVE ANESTHETICS
Phencyclidine, Ketamine, and
Dextromethorphan Intoxication
PCP and its molecular analog ketamine are dissociative anesthetics (112,113);
DXM is widely available as an antitussive in over-the-counter cough and cold
medicines (114). The chemical agents in this class are relatively old, with PCP
first synthesized just under 90 years ago and both ketamine and DXM ~50 years
ago (115). Of the three, ketamine has received considerable attention in recent
years because of its apparent ability to rapidly treat unipolar and bipolar
depression (116) and various pain syndromes (117). There is a rich literature for
the misuse of these three dissociative agents, and new psychoactive analogs
frequently appear on the illicit drug market (113). Both PCP and ketamine are
considered controlled drugs in the United States; PCP is a Schedule II and
ketamine is a Schedule III drug (118). The related drug DXM is not controlled
and is widely available as an ingredient in over 100 different over-the-counter
cough and cold medicines (119). At the recommended antitussive dose of 15-30
mg every 6-8 hours, adverse reactions are rare. However, about 5%-10% of
those of white European ethnicity are unable to demethylate DXM to
dextrorphan (an active metabolite) because of a deficit in the liver cytochrome
P450 CYP2D6 isoenzyme. Thus, in the context of megadose use of DXM, this
subset of individuals is at increased risk of toxicity from an acute excess in
DXM levels (119).
The main effects of PCP and ketamine are mediated by their action as
noncompetitive antagonists of the NMDA glutamate excitatory amino acid
neurotransmitter receptor (112,113). In addition, direct effects on other
neurotransmitter systems (such as dopamine) may occur at high doses (see
Chapter 15). In addition to NMDA antagonism, DXM has activity at the sigma
receptor, which likely contributes to its therapeutic effects as a cough
suppressant.
Psychological and Behavioral Effects of Dissociative

Anesthetic Intoxication
Dissociative anesthetics produce a range of intoxicated states that can be
grouped into three stages: stage I, conscious, with psychological effects but (at
most) mild physiological effects; stage II, stuporous or in a light coma yet
responsive to pain; and stage III, comatose and unresponsive to pain. Table 54-3
summarizes the acute psychological and behavioral effects of PCP intoxication
and overdose. The time course of psychological effects is highly variable and
unpredictable, so that even a recovering patient should be kept under observation
until all symptoms have resolved (typically at least 12 hours) (120,121). Patients
may “emerge” from one stage of intoxication to the next; that is, a stuporous or
comatose patient in stage II or III may enter stage I and become agitated and
delirious (120,121). Similarly, a conscious patient in stage I may suddenly
become comatose. The entire clinical episode may require up to 6 weeks to
resolve.
The psychiatric manifestations of stage I intoxication can resemble a variety
of psychiatric syndromes, making differential diagnosis difficult in the absence
of toxicology results or a history of recent PCP, ketamine, or DXM intake.
Common syndromes seen in treatment settings include delirium, psychosis
without delirium, catatonia, hypomania with euphoria, and depression with
lethargy. Agitated or bizarre behavior, with increased risk of violence, can occur
with any psychiatric presentation (120–122). Because of the analgesic effect of
PCP, patients may not report the existence of even serious injuries (which may
be self-inflicted).
Clinically significant psychological and behavioral effects of DXM begin to
occur at approximately five times the therapeutic dose (119). These effects can
be grouped into four dose-dependent plateaus (Table 54-5).
TABLE 54-5 Psychological and Behavioral Effects of

DXM Intoxication
Adapted from Schwartz RH. Adolescent abuse of dextromethorphan. Clin Pediatr. 2005;44(7):565-568.
Medical Effects of Dissociative Anesthetic Intoxication

Intoxication at the mild stage I desired by persons using dissociative anesthetic
substances is associated with few serious medical complications (see Table 54-
4). Common medical effects at this stage include nystagmus (especially
horizontal), tachycardia, increased blood pressure, ataxia, dysarthria, numbness,
increased salivation, and hyperreflexia. Higher stages are associated with severe
medical effects, including hypertension, stroke, cardiac failure, seizures,
rhabdomyolysis, acute renal failure, coma, and death (27).
The acute effects of ketamine tend to be less severe and of shorter duration
than those of PCP, possibly due to its shorter half-life (116). Nystagmus occurs
less often than with PCP (116).
Management of Psychological and Behavioral Effects of

Dissociative Anesthetic Intoxication
Treatment of intoxication with dissociative anesthetics is largely supportive and
aimed at controlling or reversing specific signs and symptoms (123). No
clinically useful antagonist is yet available. The anticonvulsant lamotrigine (300
mg daily), which inhibits glutamate release, reduced the psychological and
cognitive effects of ketamine in a small experimental trial (124). Mild stage I
intoxication is best treated without medication. The patient should be isolated in
a quiet room with unobtrusive observation and minimal external stimuli.
Frequent or intrusive contact or aggressive medical intervention may worsen the
situation and should be avoided. Reassuring, reality-oriented communication
(“talking down”) rarely works with such patients (68). Urine acidification and
diuretics may increase renal clearance of PCP but are of doubtful clinical utility
at this level of intoxication and may exacerbate myoglobinuric renal failure
(27,122). Benzodiazepines should be used if medication is needed to control
severe anxiety, agitation, or psychotic behavior (27), although they may delay
renal clearance of PCP at high doses (122).
If benzodiazepines are insufficient to control psychosis, high-potency first-
generation antipsychotics, such as haloperidol or droperidol, or second-
generation antipsychotics, such as risperidone or olanzapine, may be used
(125,126). They are less likely than other antipsychotics to produce
anticholinergic or cardiovascular side effects that may exacerbate PCP’s own
anticholinergic and cardiovascular effects. No clinical trials have directly
compared the efficacy and safety of first- versus second-generation
antipsychotics or of benzodiazepines versus antipsychotics.
Management of Medical Effects of Dissociative

Anesthetic Intoxication
The mild medical effects commonly associated with stage I intoxication usually
do not need specific medical treatment.
Tachycardia and hypertension can be treated with adrenergic blockers such
as labetalol or calcium channel blockers such as verapamil, although there are no
controlled trials to substantiate their efficacy. Severe hypertension can be treated
with IV nitroprusside (27).
Stage II and III intoxications are medical emergencies that require treatment
in a comprehensive medical setting to maintain life-support functions until the
drug has been eliminated from the body (118). Tables 54-6 and 54-7 summarize
medical treatment for acute PCP intoxication. In this context, increasing the
renal clearance of PCP with forced diuresis and urine acidification (pH < 5) may
be helpful (68), although this may exacerbate myoglobinuric renal failure (27).
This can be done by administering ammonium chloride—2.75 mEq/kg in 60 mL
of saline every 6 hours through a nasogastric tube—and 2 g of IV ascorbic acid
in 500 mL of IV fluid every 6 hours (128). IM ascorbic acid also has been used
successfully (128). Caution should be exercised to avoid causing metabolic
acidosis, especially in the presence of drugs such as barbiturates and salicylates,
whose renal clearance is delayed by acidification. Activated charcoal may be
helpful, but induced vomiting or gastric lavage is not (27,127,128). Dialysis is
not helpful because these agents have a large volume of distribution.
TABLE 54-6 Procedures for Managing Acute PCP

Intoxication
From Milhorn TH. Diagnosis and management of phencyclidine intoxication. Am Fam Phys.
1991;43(4):1293-1302.
TABLE 54-7 Medications for Treating Acute PCP

Intoxication
From Milhorn TH. Diagnosis and management of phencyclidine intoxication. Am Fam Phys.
1991;43(4):1293-1302.
DXM toxicity may result from the other ingredients found in cough or cold
preparations (eg, acetaminophen, pseudoephedrine, phenylephrine, guaifenesin,
antihistamines) (119). The evaluation and treatment of patients with suspected
DXM overdose must attend to the possibility of acetaminophen or other
concomitant toxicities.
Dissociative Anesthetic Withdrawal

Although a dissociative anesthetic withdrawal syndrome is not recognized in the
DSM-5 (80), about one-fourth of persons using PCP report withdrawal
symptoms (121), including depression, anxiety, irritability, hypersomnolence,
diaphoresis, and tremor. It is not clear to what extent these represent a true
withdrawal syndrome. DXM withdrawal has been associated with craving,
dysphoria, and insomnia (120). Tricyclic antidepressants such as desipramine
may reduce the psychological symptoms associated with discontinuation of PCP
use, but there is no evidence that such treatment improves the outcome of PCP
addiction (129). The efficacy of SSRIs, which would be safer in this context, is
unknown.
Prolonged Psychiatric Sequelae

Hallucinogens and dissociative anesthetics (PCP and ketamine) have the
potential to trigger psychiatric sequelae that last beyond the period of acute
intoxication, including prolonged states of anxiety, depression, psychosis, and
cognitive dysfunction. The risk of a prolonged psychiatric reaction appears to
depend on several factors: the patient’s premorbid psychopathology, the number
of prior exposures to the drug, and past use of multiple drugs (68,74). Prolonged
reactions occasionally are reported in apparently well-adjusted individuals with
no obvious risk factors. Prolonged psychotic reactions to PCP are almost always
associated with premorbid psychopathology (126).
Treatment of prolonged anxiety or depression usually is psychosocial but
may involve medication if symptoms become sufficiently severe. Treatment of
prolonged psychosis essentially follows guidelines for treatment of chronic
functional psychosis. Patients may present with wide-ranging symptomatology:
apathy, insomnia, hypomania, dissociative states, formal thought disorder,
hallucinations, delusions, and paranoia. An observation period of at least several
days with no or minimal medication (such as sedatives) is helpful to ensure an
accurate diagnosis.
The term “flashback” (hallucinogen persisting perception disorder in the
DSM-5) has been given to brief episodes (often lasting a few seconds) in which
perceptual aspects of a previous hallucinogenic drug experience are
unexpectedly reexperienced after acute intoxication has resolved. Flashbacks are
associated principally with LSD, although they can occur after use of other
hallucinogens, MDMA, PCP, and, occasionally, marijuana (74). Flashbacks can
precipitate considerable anxiety, particularly if the original drug experience had
negative overtones. Reexperience of perceptual effects may be accompanied by
somatic and emotional components of the original experience. Flashbacks may
occur spontaneously or be triggered by stress, exercise, another drug (such as
marijuana), or a situation reminiscent of the original drug experience.
Flashbacks usually are brief and self-limiting. Treatment may involve no
more than alleviating anxiety with supportive reassurance. Over time, flashbacks
tend to decrease in frequency, duration, and intensity, as long as no further
hallucinogens are taken (68).
There have been no clinical trials of pharmacological treatment for
flashbacks (74). Benzodiazepines are helpful in treating secondary anxiety.
Small case series suggest that clonazepam, clonidine, and haloperidol may be
helpful, whereas case reports suggest that phenothiazines, risperidone, and
SSRIs may worsen the condition.
Prolonged psychiatric sequelae also include dissociative drug-induced
cognitive deficits and depressed mood. For example, a number of studies have
consistently demonstrated ketamine-induced cognitive dysfunction (129–133);
depressed mood has also been identified in persons with active ketamine use
(132,133). Conversely, one study found no compelling evidence of long-term
ketamine-induced changes in cognitive function (135), while another (136)
proposed that a lower level of education in persons who use ketamine
contributed to the apparent ketamine-induced cognitive impairment. A recent
study of 100 persons with current or past ketamine use in Hong Kong (135),
which controlled for level of education, demonstrated deficits in mental and
motor speed, visual and verbal memory, and executive function in persons with
current (N = 49) but not with past use (no use for the past 30 days, N = 51)
(135). Significant increases in depression (Beck Depression Inventory) were
found in 72% of the persons with current ketamine use (135). The above studies
collectively suggest that repeated ketamine use produces cognitive deficits as
well as depressed mood in the majority of persons actively using ketamine,
though not in those who had prior use (136); the issue of reversibility remains
unclear. Recent neuroimaging studies of persons chronically using ketamine
found reduced frontal gray matter volume (137) and bilateral frontal and left
temporoparietal white matter abnormalities (138).
INHALANTS
Inhalant Intoxication
Inhalants are a chemically heterogeneous group of volatile hydrocarbons (found
in glue, fuel, paint, aerosol propellant, and other products) that can be inhaled for
psychoactive effect (139,140). Inhalant intoxication produces initial euphoria or
“rush,” followed by lightheadedness, excitability, and perceptual changes
(139,140). Significant mood changes or cognitive impairment is rare. Higher
doses or more prolonged exposure may cause dizziness, slurred speech, and
motor incoordination, followed by drowsiness and headache. Intoxicated persons
rarely seek medical attention, in part because exposure tends to be self-limited
and the duration of effect from a single exposure is usually only a few minutes.
Even a single episode of inhalant use can result in sudden death (141,142).
Inhalant-induced brain neurotoxicity (143,144), especially to the white matter
(145), as well as kidney, heart, and nerve damage (146,147), may complicate the
clinical presentation of acute inhalant intoxication.
There is no specific treatment for inhalant intoxication (148). The patient
should be assessed, stabilized, and monitored (especially cardiopulmonary status
and hydration) in accordance with their clinical condition. Inhalants may
sensitize the myocardium, so pressor medications and bronchodilators are
relatively contraindicated.
Inhalant Withdrawal
Inhalant withdrawal is not a recognized clinical syndrome in the DSM-5 (80), yet
a growing literature describes an inhalant-induced withdrawal process. One
study found that over 11% of patients evaluated for inhalant use reported
withdrawal-like symptoms (149). Presumed inhalant withdrawal symptoms
include depressed mood, fatigue, anxiety, difficulty concentrating, tachycardia,
diaphoresis, muscle trembling or twitching, increased tearing and nasal
secretions, headache, nausea and vomiting, and craving for inhalants
(139,149,150). Some persons using inhalants report further use of these
substances to avoid experiencing these symptoms, suggesting that symptoms
served as negative reinforcement for continued use (150). There is no specific
treatment for inhalant withdrawal (148).
CLUB DRUGS
“Club drugs” are a pharmacologically heterogeneous group of drugs associated
with a youth subculture that revolves around late-night dance parties known as
“raves” or “trances” (151). The illicit use of these substances was popularized in
this setting because of their perceived ability to enhance the sensory experience
and allow for long periods of dancing to repetitive music. Common club drugs
include MDMA (“ecstasy”), an amphetamine analog with stimulant and
hallucinogenic properties, and GHB and flunitrazepam (Rohypnol, no longer
marketed in the United States, Canada, or UK), both of which are CNS
depressants. Pharmacological interactions from the concurrent use of multiple
club drugs substantially increase the risk of toxicity (152).
MDMA (“ECSTASY”)
“Ecstasy” is the common street name for MDMA (see Chapter 14). Related
amphetamine analogs such as 3,4-methylenedioxyethylamphetamine (“eve”);
3,4-methylenedioxyamphetamine; and N-methyl-1-(3,4-
methylenedioxyphenyl)-2-butanamine may also be present in street preparations.
The effects of MDMA are those of a stimulant combined with a mild
hallucinogen (153,154). “Herbal ecstasy” often refers to preparations containing
the stimulant ephedrine. “Liquid ecstasy” is a street name for GHB (see the
following section).
MDMA often is taken concurrently with other drugs, such as LSD (in a
combination called “candyflipping”), for enhanced effect. DXM (available in
over-the-counter cough medicines) is a frequent concomitant drug and may be
substituted for MDMA in street preparations (120). “Stacking” is the practice of
taking multiple MDMA doses over a short period, often alternating with other
drugs to enhance the experience. Menthol, camphor, or ephedrine may be
applied to the nasal mucosa or chest wall to enhance the drug experience (153).
MDMA has good oral bioavailability and readily crosses the blood–brain
barrier (153,154). The onset of action is within 30 minutes; peak plasma
concentrations are achieved in 1-3 hours (154). The elimination half-life is 7-8
hours. Because MDMA is a weak acid, this is delayed to 16-31 hours with
alkaline urine. MDMA is metabolized by several hepatic microsomal enzymes,
chiefly CYP2D6.
Individuals who are genetically deficient in CYP2D6 (up to 10% of whites)
are theoretically at increased risk of developing MDMA toxicity (155), though
some studies suggest this risk is minimal (156).
MDMA appears to have nonlinear kinetics because the higher affinity
enzymes become saturated at relatively low drug concentrations (157). This
results in disproportionately large increases in drug concentrations in response to
small increases in dose (155) and may account for the poor correlation between
plasma concentration and toxicity (158). However, psychological effects may
not increase proportionally with plasma concentrations, suggesting acute
tolerance (153). A major MDMA metabolite is 3,4-methylenedioxyamphetamine
(MDA), which also is pharmacologically active and has a longer elimination
half-life of 16-38 hours (159).
MDMA Intoxication
The diagnosis of MDMA intoxication is made by history of drug intake and/or
analysis of unused drug. Most signs and symptoms are not specific to MDMA
but resemble those of stimulants or hallucinogens. MDMA is not detected by
routine urine or blood drug screens, which may be positive for amphetamines
(products of MDMA metabolism) (154,155).
Gastric lavage with activated charcoal may be helpful within the first hour
after ingestion, especially if other drugs also have been taken. Induced emesis is
not recommended because of the risk of CNS depression. Acidification of urine
would quicken MDMA elimination but usually is contraindicated because it
increases the risk of metabolic acidosis, thereby exacerbating renal toxicity from
rhabdomyolysis.
Psychological and Behavioral Effects of MDMA

Intoxication
Low to moderate oral doses of MDMA (50-150 mg) typically produce an intense
initial effect (known as “coming on” or “rush”), especially if taken on an empty
stomach, that may last 30-45 minutes (160). Desired effects include increased
wakefulness and energy, euphoria, increased sexual desire and satisfaction,
heightened sensory perception, sociability, and increased empathy and sense of
closeness to others (157,160,161). The initial phase is followed by several hours
of less intense experience (“plateau”), during which repetitive dancing is
common. Persons using MDMA often start to “come down” 3-6 hours after
ingestion (154).
Undesired effects may occur with repeated use or at higher doses (162).
These include hyperactivity, fatigue, insomnia, anxiety, agitation, impaired
decision-making, flight of ideas, hallucinations, depersonalization,
“derealization,” and bizarre or reckless behavior. Some persons develop panic
attacks, brief psychotic episodes, or delirium, which usually resolve rapidly as
the drug effect wears off (163). Initial treatment is the same as for hallucinogen
intoxication: placement in a quiet, reassuring environment, with observation to
reduce the risk of unintended self-injury. Physical restraints are contraindicated
because they may exacerbate anxiety and increase the risk of rhabdomyolysis. If
severe or persisting symptoms require medication, benzodiazepines are
preferred. Antipsychotics should be avoided as much as possible because they
increase the risk of hyperthermia and seizures. A high-potency antipsychotic
such as haloperidol should be used if necessary. The role of second-generation
antipsychotics remains unclear. A few persons who use MDMA may develop
persisting depression or recurrent psychotic symptoms or panic attacks, which
require psychiatric treatment.
Medical Effects of MDMA Intoxication
The acute physical effects of MDMA at low to moderate doses resemble those of
a stimulant: increased muscle tension, jaw clenching, tooth grinding (bruxism),
restlessness, insomnia, ataxia, headache, nausea, decreased appetite, dry mouth,
dilated pupils, and increased heart rate and blood pressure (157,160,161). Doses
>200 mg are associated with life-threatening toxicities that can be grouped into
four major syndromes (164). The most dangerous is hyperthermia, which results
from a combination of direct thermogenic effects of the drug (probably via
adrenergic mechanisms), increased physical activity (as through vigorous
dancing), warm environment (as in a crowded, poorly ventilated dance club),
and disruption of thermoregulation by the drug, often exacerbated by
dehydration (75,165). The syndrome may resemble that of severe heatstroke.
The high body temperature causes rhabdomyolysis (with resulting
myoglobinuria and renal failure), liver damage, or disseminated intravascular
coagulation (resulting in hemorrhage). Treatment is based on early recognition,
close monitoring of serum creatine kinase levels (to detect rhabdomyolysis), and
reversal of the hyperthermia. Core body temperatures >102°F call for urgent
measures such as ice water sponging, gastric or bladder lavage with cool liquids,
and intravenous infusion of chilled saline. Muscle paralysis with intubation may
be required for refractory, ongoing rhabdomyolysis. Rhabdomyolysis treatment
includes vigorous hydration and alkalinization of the urine to minimize
myoglobin precipitation in the renal tubules.
Benzodiazepines help control both the hyperthermia and agitation.
Antipsychotics should be avoided because they interfere with heat dissipation
and lower the seizure threshold. Recent case series suggest that dantrolene (1
mg/kg IV) may be helpful. Because of similarities between MDMA toxicity and
the serotonin syndrome (see the following section entitled Serotonin Syndrome),
serotonin antagonists such as methysergide and cyproheptadine have been used
successfully.
Acute hepatic toxicity from MDMA may be related to metabolism into
reactive intermediaries that deplete hepatic glutathione, resulting in cell death
(157,159). The clinical picture can vary from a mild hepatitis (marked by
enlarged, tender liver and elevated serum liver enzymes) that resolves
spontaneously over several weeks to fulminant liver failure requiring
transplantation. Liver toxicity may be exacerbated by hyperthermia.
Acute cardiovascular toxicity from MDMA is the result of increased
catecholamine activity (157,166). This may cause hypertension, with risk of
blood vessel rupture and hemorrhage, or tachycardia and cardiac arrhythmia.
The preferred treatment is an adrenergic antagonist with both alpha- and beta-
blocking activities, combined with a vasodilator such as nitroglycerin or
nitroprusside if needed to control blood pressure. A pure beta-adrenergic blocker
should be avoided because of the remaining unopposed alpha-adrenergic
stimulation, resulting in vasoconstriction and worsening hypertension.
Hypertensive crisis unresponsive to mixed adrenergic blockers and vasodilators
should be treated with an alpha-adrenergic antagonist such as phentolamine (33).
Cardiac ischemia or arrhythmia should be treated by standard clinical protocols.
Agitation should be controlled with a short-acting benzodiazepine such as
lorazepam.
In addition to direct MDMA-mediated neurotoxicity (167), acute toxicity
can result from hyponatremia (“water intoxication”), which may cause seizures
and intracranial fluid shifts that compress the brain stem into the foramen
magnum (75). The hyponatremia is caused by loss of sodium in sweat (as during
vigorous dancing in a warm environment) and hemodilution from drinking large
amounts of water and the antidiuretic effect of MDMA. The conservative initial
treatment is fluid restriction. Profound hyponatremia has been treated with
hypertonic saline solution (168). Intravenous benzodiazepines should be used to
control seizures.
MDMA Withdrawal
Symptoms during the first few days after MDMA use may resemble a mild form
of stimulant withdrawal or “crash,” with depression, anxiety, fatigue, and
difficulty concentrating (75,157). These usually resolve without treatment.
Prevalence of withdrawal (DSM-IV criteria) was 1% in a convenience sample of
214 Australian MDMA users (169).
Medical Effects of MDMA Withdrawal

There is no evidence of a physically prominent or distinctive withdrawal
syndrome associated with MDMA that would require specific pharmacological
treatment. Persons withdrawing from MDMA may complain of muscle pain and
stiffness in the jaw, neck, lower back, and limbs for the first 2-3 days after use
(75,157), which may be the result of MDMA-induced muscle tension and the
vigorous dancing often associated with MDMA use. There is some evidence of
increased variability of heart rate and blood pressure for several days after
MDMA use.
GAMMA HYDROXYBUTYRATE
GHB (sometimes termed “liquid ecstasy”) is a naturally occurring metabolite of
the neurotransmitter gamma-aminobutyric acid (GABA) that may itself function
as an agonist at both the GABA-B receptor and a putative GHB receptor
(170,171). It is approved for the treatment of narcolepsy (sodium oxybate
(Xyrem), Schedule III controlled substance) but is also used recreationally. GHB
became popular in the late 1980s, when it was marketed and sold in health food
stores as a supplement for body building and other putative health effects. Use of
GHB increased well beyond the supplement market, in part because of its
reputed euphoric, aphrodisiac, disinhibitory, and amnestic effects. GHB’s short
duration of action, minimal “hangover” effects, and nondetectability by standard
drug screens contributed to its popularity. The legal precursors gamma-
butyrolactone (GBL, an industrial solvent found in floor strippers and some
household products) and 1,4-butanediol (1,4-BD), which are readily metabolized
to GBH in the body, are also used recreationally (172), as are structural analogs
such as β-phenyl-GABA (phenibut), developed in the Soviet Union as a
sedative/anxiolytic but now readily available in the United States and Europe as
a nutritional supplement (173).
GHB is taken orally as a liquid or in a powder mixed into drinks. A typical
dose is 1-3 teaspoons or capfuls, though variations in concentration make it
challenging to determine the actual dosage of GHB in recreational preparations.
GHB is rapidly absorbed from the gastrointestinal tract and readily crosses the
blood–brain barrier. Effects begin within 15 minutes of ingestion and last 2-4
hours (174). The blood elimination half-life is about 30 minutes, largely because
of rapid redistribution into other tissues.
GHB Intoxication
The diagnosis of GHB intoxication is based on clinical suspicion, a history of
drug ingestion, or analysis of unused drug. The signs and symptoms of GHB
intoxication are not specific and are difficult to differentiate from other CNS
depressants. GHB is not detected by routine drug toxicology assays. Definitive
detection requires fluid analysis utilizing gas chromatography/mass spectrometry
(175), which commonly takes 7-14 days.
There is no proven antidote for GHB intoxication. Physostigmine, naloxone,
and flumazenil have reversed some GHB effects in small case series or animal
studies (176) but should be considered experimental. Gastric lavage usually is
not helpful because of rapid gastrointestinal absorption, but activated charcoal
may be.
Psychological and Behavioral Effects of GHB

Intoxication
The desired acute effects of GHB at low oral doses (<20 mg/kg) include
relaxation, euphoria, sedation, disinhibition, sociability, and anterograde amnesia
that has been linked to sexual assault (177–179). Higher doses produce
somnolence, confusion, and hallucinations (180). Unintended overdose may
occur because of GHB’s very steep dose–response curve, narrow therapeutic
index, and the great variability in potency of street preparations. Persons using
GHB for the first time often underestimate the potency of GHB. The effects are
prolonged and intensified when taken with other CNS depressants, such as
alcohol. Patients recovering from acute GHB intoxication may wake up abruptly
with a clear sensorium or may go through a brief period of agitation and
combativeness.
Medical Effects of GHB Intoxication

Low to moderate oral doses of GHB may cause headache, dizziness, ataxia,
hypotonia, and vomiting. Higher doses (>30 mg/kg) may cause incontinence,
myoclonic movements, bradycardia, hypotension, hypothermia, generalized
tonic–clonic seizures, and coma (27,180). Concurrent ingestion of other drugs,
including alcohol, substantially increases the severity of GHB intoxication (180).
Most patients with pure GHB intoxication recover completely within several
hours with supportive care and do not require intubation. However, death may
result from respiratory depression, so that intubation and mechanical ventilation
may be indicated in severe cases. Seizures should be controlled with
benzodiazepines, symptomatic bradycardia with atropine, and symptomatic
hypotension with intravenous saline.
GHB Withdrawal
Cessation of chronic GHB or GBL use leads to a discrete withdrawal syndrome
resembling that of sedative–hypnotic withdrawal, presumably mediated by
unopposed excitation in the neurotransmitter systems ordinarily inhibited by
GABA-B (and GHB) receptors (180). Anxiety, restlessness, insomnia, tremor,
nystagmus, tachycardia, and hypertension usually appear 2-12 hours after the
last dose (181–183). Mild symptoms usually resolve gradually over 1-2 weeks.
More severe withdrawal may cause delirium with hallucinations, psychosis,
agitation, and autonomic instability (180) and may present similarly to delirium
tremens (182). GHB withdrawal seizures are rare but have been reported (185).
Physical dependence may develop within 1 week of repeated daily dosing.
Most cases of GHB withdrawal can be managed with a long-acting
benzodiazepine, tapering the dose after the symptoms are controlled (as for
sedative–hypnotic withdrawal) (184). Severe cases may require high doses
(several 100 mg) or parenteral administration. Patients unresponsive to
benzodiazepines may benefit from barbiturates, slow tapering with GHB itself
(185), or baclofen (30-60 mg daily) (186), although toxic interactions between
GHB and high doses of baclofen have been reported (187). It has been proposed
that a single class of medications, including benzodiazepines, gabapentin, or
antipsychotics, may not provide sufficient protection to avoid “life threatening
complications” (182). Because of the unpredictability of GHB withdrawal and
vulnerability to severe complications such as delirium and potential lethality
(174,180,181,188), withdrawal management is best undertaken in a hospital
setting. Mild withdrawal syndromes may be managed in an outpatient setting
with close supervision (184).
MISUSE OF HERBS
Herbs are plants used for medicinal, culinary, or spiritual purposes. Many herbs
contain psychoactive compounds with stimulant, anxiogenic, anxiolytic,
hallucinogenic, euphoric, or dissociative effects (189,190). These properties
have long been recognized in many indigenous cultures.
The psychoactive profile of herbs, combined with the fact that production,
sale, and purchase of most herbs are largely unregulated, has contributed to a
growing market for their recreational use (190). Internet distribution of herbs
makes them widely available to minors (191). The perception that herbs are safer
than illicit drugs, coupled with the absence of clearly established dosing
parameters, contributes to their misuse (192). Routine toxicology screens do not
detect many of these substances, so that identifying specific intoxication
syndromes may be challenging. Accurate diagnosis may rest on collateral
information from family, friends, and first responders, in addition to a thorough
clinical examination.
Intoxication
Herbs prone to misuse often contain multiple psychoactive compounds, so that
intoxication syndromes may not fit neatly into distinctive classifications. For
clarity, these herbs may be categorized as predominantly hallucinogenic or
stimulating. Table 54-8 describes basic characteristics of some of the commonest
herbs being misused.
TABLE 54-8 Commonly Misused Herbal Drugs
DMT, N,N-dimethyltryptamine; GABA, γ-aminobutyric acid; LSA, lysergic acid amide; MA,
methamphetamine; MAO, monoamine oxidase.
Sources: Richardson WH, Slone CM, Michels JE. Herbal drugs of abuse: an emerging problem. Emerg
Med Clin N Am. 2007;254:35-57; Halpern JH. Hallucinogens and dissociative agents naturally growing in
the United States. Pharmacol Ther. 2004;102:131-138.
Hallucinogenic herbs achieve their psychotomimetic effects principally through

activity at serotonergic or cholinergic receptors. Stimulating herbs generally
augment the activity of norepinephrine or dopamine. Thus, the manifestations
and management of intoxication syndromes for this varied group of substances
generally follow that for hallucinogen or stimulant intoxication.
Management of Psychological, Behavioral,

and Medical Effects
Management of intoxication with hallucinogenic herbs is largely supportive
because most symptoms, including psychosis, are self-limited. The goal is to
maintain safety, preventing patients from physically harming themselves or
others. A quiet environment, with calm counseling and guidance, often avoids
the need for pharmacological interventions. Medications with anticholinergic
properties are best avoided to minimize exacerbating substance-induced
delirium. Physical restraints should be avoided because they increase
psychological distress and may contribute to rhabdomyolysis. Patients who are
agitated, in severe panic, or having distressing psychotic symptoms may be
relieved by benzodiazepines (eg, lorazepam 2 mg PO/IM every 1-2 hours,
titrated to mild sedation). In cases where predisposing factors or heavy chronic
use contributes to prolonged psychotic symptoms, antipsychotic agents may be
useful.
Management of intoxication with stimulant herbs is similar to that with
hallucinogenic herbs, except that the former are more likely to generate
hyperexcitable, agitated, and psychotic states. Patients with unstable vital signs
should be closely monitored, including cardiac function, blood pressure, and
body temperature. Beta-adrenergic blockers are generally avoided due to
concern about unopposed alpha-adrenergic activity.
With one exception, there are no specific antidotes to intoxication with
psychoactive herbs. Intoxication with herbs having anticholinergic activity (eg,
jimsonweed) has been successfully treated with physostigmine, a short-acting
acetylcholinesterase inhibitor (176). Severe intoxication with betel nut, which
has cholinergic activity, can be treated with atropine, a cholinergic antagonist.
Withdrawal
Most persons withdrawing from psychoactive herbs do not consume large
enough amounts for long enough periods to develop physical dependence or a
withdrawal syndrome. Some persons who use khat and betel nuts do experience
a withdrawal syndrome, often including irritability, fatigue, and rhinorrhea (190).
Protracted withdrawal symptoms (eg, psychosis, depression, anxiety) should be
treated symptomatically while the patient is evaluated for an underlying
psychiatric disorder.
FLUNITRAZEPAM
Flunitrazepam (Rohypnol, also known as “roofies” or the “date rape pill”) is a
potent, fast-acting benzodiazepine that frequently causes anterograde amnesia
(193). It is legally manufactured and marketed in Europe and Latin America but
is illegal in the United States, Canada, and several European countries because
of its association with “date rape,” although the epidemiological evidence for
this is limited (193). Flunitrazepam is difficult to detect with routine toxicology
screens because of the low concentration needed for pharmacological effects.
Flunitrazepam Intoxication
Flunitrazepam intoxication resembles intoxication with other benzodiazepines
and features sedation, disinhibition, anterograde amnesia, confusion, ataxia,
bradycardia, hypotension, and respiratory depression (193). Overdose, alone
and/or particularly concurrently with alcohol ingestion can be lethal (193). When
respiratory depression or circulatory compromise is severe, the benzodiazepine
antagonist flumazenil (Romazicon) may be used, albeit cautiously. Flumazenil
precipitates acute withdrawal in patients who are physically dependent on
benzodiazepines and lowers the seizure threshold, thus increasing the risk of
withdrawal seizures. Flumazenil is effective for about 20 minutes, so that
repeated dosing is necessary to avoid resedation by flunitrazepam.
Flunitrazepam Withdrawal
A typical sedative–hypnotic withdrawal syndrome can develop after cessation of
chronic flunitrazepam use. Withdrawal symptoms can develop up to 36 hours
after the last dose and include anxiety, restlessness, tremors, headache, insomnia,
and paresthesias. Treatment of withdrawal involves supportive measures and
substitution with cross-tolerant medications such as lorazepam or clonazepam,
followed by gradual tapering.
SEROTONIN SYNDROME
The serotonin syndrome is a potentially lethal condition associated with
increased serotonergic activity in the CNS. Substances that increase serotonin
activity, directly (MDMA), indirectly (SSRIs), or in combination, can trigger this
syndrome. The serotonin syndrome is a triad of signs and symptoms, consisting
of mental status changes (eg, anxiety, confusion, agitation, lethargy, delirium,
coma), autonomic hyperactivity (eg, low-grade fever, tachycardia, diaphoresis,
nausea, vomiting, diarrhea, dilated pupils, abdominal pain, hypertension,
tachypnea), and neuromuscular abnormalities (eg, myoclonus or clonus,
nystagmus, hyperreflexia, rigidity, trismus, tremor) (194,195). The clinical
presentation is highly variable, making diagnosis difficult, but neuromuscular
signs are usually prominent, particularly in the lower extremities (194–198). The
Hunter Toxicity Criteria Decision Rules are 84% sensitive and 97% specific for
serotonin syndrome when compared with the gold standard of diagnosis by a
medical toxicologist (197). The Hunter Criteria include recent ingestion of a
serotonergic agent and at least one of the following:
1. Spontaneous clonus
2. Inducible clonus plus agitation or diaphoresis
3. Ocular clonus plus agitation or diaphoresis
4. Tremor plus hyperreflexia
5. Hypertonia plus temperature above 38°C plus ocular clonus or inducible
clonus
The differential diagnosis includes neuroleptic malignant syndrome (with which

it is most commonly confused), sepsis, heat stroke, delirium tremens, and
sympathomimetic or anticholinergic poisoning (198). Patients with neuroleptic
malignant syndrome differ from those with serotonin syndrome in that they are
more likely to present with extrapyramidal signs and autonomic instability and
rarely present with the neuromuscular changes common in serotonin syndrome
(198).
The serotonin syndrome is the result of excessive stimulation of 5-HT2A,
possibly with some contribution from 5-HT1A, receptors. This occurs through
several different pathways: activation of serotonin receptors by agonists,
enhanced release of serotonin (by MDMA or amphetamines), decreased
presynaptic serotonin reuptake (by cocaine or SSRI antidepressants), decreased
serotonin metabolism (by amphetamines or monoamine oxidase inhibitors), and
increased serotonin synthesis. The serotonin syndrome is most commonly seen
after ingestion of two or more drugs with such actions but also may occur with a
single drug.
The onset of the serotonin syndrome is within minutes to hours of
medication initiation, increase in dose, or overdose. Laboratory abnormalities are
nonspecific; no test confirms the diagnosis. Elevated creatine phosphokinase,
liver transaminases, white blood cell count, serum bicarbonate, and evidence of
disseminated intravascular coagulation occur in severe cases (194). In severe
cases, or in the absence of appropriate diagnosis and treatment, there may be
progression to rhabdomyolysis, hyperthermia, renal failure, disseminated
intravascular coagulation, and death.
Effective treatment of the serotonin syndrome requires early identification,
immediate discontinuation of all serotonergic medications, close monitoring, and
supportive care, usually including intravenous hydration. Such treatment usually
results in a benign, self-limited course; many cases resolve within 24 hours.
Muscle rigidity and spasm should be controlled with benzodiazepines to prevent
rhabdomyolysis. Management of hyperthermia is vital to mitigate complications
such as seizures, disseminated intravascular coagulation, and metabolic acidosis.
Severe forms of the syndrome require more aggressive measures, including
neuromuscular blocking agents, mechanical ventilation, and external cooling.
Antipyretics are generally unhelpful because the source of hyperthermia is
muscular activity, not alterations in hypothalamic temperature set point
(196,197). Treatment with a 5-HT2A receptor antagonist (eg, cyproheptadine,
olanzapine, chlorpromazine) has been effective in case series but has not yet
been evaluated in controlled clinical trials.
WITHDRAWAL FROM MULTIPLE

DRUGS
Multiple Sedative–Hypnotics
Withdrawal from dependence on multiple sedative–hypnotic agents, including
alcohol, is best managed in the same way as withdrawal from a single such drug:
by using tapering dosages of a single, longer-acting sedative–hypnotic (5,199). It
usually is safest to focus on managing withdrawal of the longer-acting drug. The
time course of withdrawal from multiple sedative–hypnotics is more
unpredictable than from single drugs; for example, there may be a bimodal time
course of symptomatology if one drug is short acting and the other is longer
acting. The rate at which the dose is tapered usually should not exceed 10% per
day. Successful withdrawal is facilitated by use of an anticonvulsant such as
carbamazepine (200), although such use has not been evaluated in multiple drug
withdrawal.
Sedative–Hypnotics With Other Drugs

In the pharmacological management of patients withdrawing from both
sedative–hypnotics and CNS stimulants, it is preferable to treat the sedative–
hypnotic withdrawal first because this poses the greatest difficulty and medical
risk. For concurrent addiction to sedative–hypnotics and opiates, concurrent
pharmacological treatment is recommended (6,200). The patient may be
stabilized on an opioid (preferably oral methadone, although codeine can be used
if methadone is not available) at the same time that the sedative–hypnotic dose is
tapered by 10% per day. After the sedative–hypnotic withdrawal is completed,
opioid withdrawal can begin. Clonidine has been suggested as adjunctive
treatment for such mixed sedative–hypnotic and opiate withdrawal, because it
can alleviate withdrawal symptoms from both drug classes, but this has not been
evaluated systematically.
POPULATION-SPECIFIC
CONSIDERATIONS
Neonates
Neonatal drug exposure is a substantial public health problem. Many addictive
drugs are readily transferred from the maternal circulation across the placenta to
the fetus. Thus, perinatal drug use by the mother raises the possibility of drug
intoxication or withdrawal in the newborn (201–203). Obtaining an accurate
maternal drug use history for the period preceding delivery is essential.
Meconium is the most accurate substrate for neonatal toxicology through the 3rd
to 4th day of life, but such testing is not widely available.
Neonatal signs and symptoms of drug intoxication or withdrawal often are
nonspecific, including sedation, irritability, restlessness, hypertonia,
hyperreflexia, tremors, poor feeding, abnormal sleep patterns, respiratory
difficulty, and seizures. Stimulants (such as cocaine), marijuana, LSD, and PCP
all have been associated with a neonatal withdrawal syndrome, although one that
usually is less intense than the opiate withdrawal syndrome (204).
Perinatal use of stimulants by the mother is associated with either
bradycardia or tachycardia in the newborn (205). The additive cardiovascular
effects of the stimulant and the normal catecholamine surge during labor may
cause fetal distress and retard delivery (203). These cardiac effects usually
resolve as the drug is eliminated from the body. Neonatal stimulant intoxication
is associated with irritability, tremors, hyperactivity, abnormal movements,
excessive sucking, and high-pitched and excessive crying for 1-2 days, followed
by a period of lethargy and hyporeactivity (206–208).
Treatment of drug-exposed newborns is largely supportive, with avoidance
of overstimulation. Pharmacological treatment should be used cautiously
because it has its own potential for morbidity. Phenobarbital is the preferred
medication for newborns with nonopioid drug withdrawal who do require
pharmacological treatment, as when seizures are a factor. A loading dose of 5
mg/kg/d is given until withdrawal is controlled, with adjustments of 10%-20%
every 2-3 days based on the response. Phenobarbital has a long half-life, so
plasma concentrations should be checked periodically to avoid drug
accumulation and overtreatment.
Older Adults
Rates of illicit drug use by the elderly are low but may be increasing (209).
There are few published data on the treatment of drug intoxication or withdrawal
in this age group. The elderly may be more susceptible to confusion and
disorientation during withdrawal and to medication-induced delirium. The
recommended dosing approach is “start low and go slow”; that is, start
medication at a lower dose, and increase the dose in smaller increments than
would be used in younger individuals.
Adolescents
Adolescence is the common age of onset for illegal drug use (210), and the
developing adolescent brain may be especially vulnerable to the neurobiological
effects of drugs (211). Adolescents experience symptoms of drug withdrawal
similar to those in adults, including physical symptoms (212). There are few
published data on the treatment of drug intoxication or withdrawal in adolescents
(213,214).
Women
Women often differ from men in their response to psychoactive drugs and to
drug use disorder treatment (215), but there has been little systematic study of
gender differences in the treatment of drug intoxication and withdrawal. Limited
anecdotal evidence suggests that pharmacological treatment for women is
similar to that for men, taking into account possible gender differences in
medication pharmacokinetics. Two topics requiring further research are the
influence of the menstrual cycle on intoxication and withdrawal and their
treatment and the effects of intoxication and withdrawal and their treatment on
pregnancy and the fetus.
ACKNOWLEDGMENTS
Dr. Wilkins is supported by the Cedars-Sinai Medical Center Lincy-
Heyward/Moynihan Endowed Chair in Addiction Medicine.
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SECTION 7
Pharmacological Interventions and

Other Somatic Therapies
CHAPTER 55
Pharmacological Interventions for
Hugh Myrick, Andrew J. Saxon and Jerome H. Jaffe
CHAPTER OUTLINE
Introduction
Medications Used to Reduce or Stop Drinking
Medications to Treat Co-Occurring Psychiatric Symptoms or Disorders in
Patients With Alcohol Use Disorder
The Use of Pharmacotherapies in the Treatment of Alcohol Use Disorder
Summary and Conclusions
INTRODUCTION
It has been well established that unhealthy alcohol use is associated with
numerous health risks (1). In the United States, unhealthy alcohol use accounted
for 1 in 10 deaths among working-age adults (2006-2009) and shortened the
lives of those who died by an average of 30 years (2,3). Despite the risks, there
is a lack of recognition and treatment of alcohol use disorder (4). Recent data
suggest that only 7.7% of individuals diagnosed with alcohol use disorder within
12 months received treatment (5). Accordingly over the past three decades, we
have seen the entry of several medications to treat alcohol use disorder. In this
chapter, we review the literature on the use of medications to reduce drinking or
prevent relapse in those with unhealthy alcohol use. Rather than reviewing the
literature exhaustively, the focus of the chapter is on developments of current
interest to the clinician or that are likely to yield important clinical advances in
the future. We also refer the reader to a number of other recent reviews that
augment the information provided here (6,7).
The first major approach to the use of medications in the treatment of
individuals with alcohol use disorders involves direct efforts to reduce or stop
drinking behavior by producing adverse effects when alcohol is consumed or by
modifying the neurotransmitter systems that mediate alcohol reinforcement.
Table 55-1 lists the four medications or formulations that use this approach and
are approved by the U.S. Food and Drug Administration (FDA) for the treatment
of alcohol use disorder. The table also shows the year of FDA approval, the
presumed mechanism of action, and the approved dosage for each of these. The
medications are discussed individually in the sections that follow. The second
main approach to the treatment of alcohol use disorder involves the treatment of
persistent psychiatric symptoms, which aims to stop or reduce drinking by
modifying the motivation to use alcohol to “self-medicate” such symptoms.
Medications for which this rationale underlies their use in the treatment of
alcohol use disorder are discussed in the latter part of this chapter.
TABLE 55-1 Medications Approved by the U.S. Food

and Drug Administration for the Treatment of Alcohol
Dependence
MEDICATIONS USED TO REDUCE OR

STOP DRINKING
Alcohol-Sensitizing Agents
Alcohol-sensitizing agents alter the body’s response to alcohol, thereby making
its ingestion unpleasant or toxic. Disulfiram (Antabuse) is the only alcohol-
sensitizing medication approved in the United States for the treatment of alcohol
use disorder and that is widely used clinically. Consequently, we focus on that
agent here.
Disulfiram inhibits the enzyme aldehyde dehydrogenase, which catalyzes the
oxidation of acetaldehyde to acetic acid. The ingestion of alcohol while this
enzyme is inhibited elevates the blood acetaldehyde concentration, resulting in
the disulfiram–ethanol reaction (DER). The intensity of the DER varies both
with the dose of disulfiram and the volume of alcohol ingested. Symptoms and
signs of the DER include warmness and flushing of the skin, especially that of
the upper chest and face; increased heart rate; palpitations; and decreased blood
pressure. They may also include nausea, vomiting, shortness of breath, sweating,
dizziness, blurred vision, and confusion. Most DERs are self-limited, lasting
about 30 minutes. Occasionally, the DER may be severe, with marked
tachycardia, hypotension, or bradycardia; rarely, it may result in cardiovascular
collapse, congestive failure, and convulsions. Although severe reactions are
usually associated with high doses of disulfiram (over 500 mg/d), combined with
more than 2 oz of alcohol, deaths have occurred with lower dosage and after a
single drink (8,9). Concern over the potential for such effects may limit
clinicians’ willingness to prescribe disulfiram.
Given its intuitive appeal, disulfiram has long been used in the treatment of
patients with alcohol use disorder (10), despite a lack of methodologically sound
evaluations demonstrating its efficacy in the prevention of relapse. However, in
selected samples of such individuals with whom special efforts, such as
supervised administration, are made to ensure compliance, these medications
may be useful. As discussed below, disulfiram may also limit the severity of
relapse when it occurs. There are no guidelines that can be offered either to
identify patients for whom disulfiram is most likely to have a beneficial effect or
to match specific psychosocial interventions with particular patients to enhance
compliance.
Its approval for use by the FDA preceded the implementation of rigorous
requirements for efficacy that now must be satisfied for a medication to be
marketed in the United States. In the controlled studies conducted, the difference
in outcome between subjects receiving disulfiram and those given placebo has
generally been modest.
The largest and most methodologically sound study of disulfiram was a
multicenter trial conducted by the Veterans Administration Cooperative Studies
Group. In that 1-year study, more than 600 male patients with (pre-DSM-5)
alcohol dependence were randomly assigned to receive either 1 mg of disulfiram
per day, 250 mg/d, or an inactive placebo (11). Patients assigned to the two
disulfiram groups were told they were receiving the medication, but neither
patients nor staff knew the dosage. Results showed that greater compliance with
the medication regimen (in all three groups) was associated with a greater
likelihood of complete abstinence. Among patients who resumed drinking, those
in the group receiving 250 mg of disulfiram reported significantly fewer
drinking days than did patients in either of the other two groups. Based on these
findings, it appears that disulfiram may be helpful in reducing the frequency of
drinking in men who cannot remain abstinent, though given the large number of
statistical analyses, it is possible that this finding arose by chance.
Disulfiram may be of clinical value in selected individuals with alcohol use
disorder with whom special efforts are made to ensure compliance. Specific
behavioral efforts to enhance compliance with disulfiram (as well as other
medications for the treatment of alcohol use disorder) include contracting with
the patient and a significant other to work together to ensure compliance and the
provision to the patient of incentives, regular reminders and other information,
and behavioral training and social support (12). A trial program of stimulus
control training, role playing, communication skills training, and recreational
and vocational counseling improved outcome in disulfiram-treated patients
compared with those receiving placebo (13). Supervision of patients being
treated with disulfiram may be an essential element in ensuring compliance and
enhancing the beneficial effects of the medication (14). In a 6-month study,
Chick et al. (15) randomly assigned patients to receive disulfiram 200 mg/d or
vitamin C 100 mg/d (ingested under the supervision of an individual chosen by
the patient) as an adjunct to outpatient alcohol treatment. Treatment with
disulfiram significantly increased abstinent days and decreased total drinks
consumed, effects that were confirmed by parallel changes in levels of the
hepatic enzyme γ-glutamyl transpeptidase (GGT).
Pharmacology and Clinical Use of Disulfiram

Disulfiram is almost completely absorbed orally. Because it binds irreversibly to
aldehyde dehydrogenase, renewed enzyme activity requires the synthesis of new
enzyme, so that the potential exists for a DER to occur at least 2 weeks from the
last ingestion of disulfiram. Consequently, alcohol should be avoided during this
period.
Disulfiram commonly produces a variety of adverse effects, including
drowsiness, lethargy, and fatigue (16). Although more serious adverse effects,
such as optic neuritis, peripheral neuropathy, and hepatotoxicity, occur rarely,
patients treated with disulfiram should be monitored regularly for visual changes
and symptoms of peripheral neuropathy and the medication discontinued if they
appear. Further, the patient’s liver enzymes should be monitored monthly or at
more frequent intervals during the first 3 months of treatment and quarterly
thereafter to identify hepatotoxic effects, which may also warrant
discontinuation of the medication. Psychiatric effects of disulfiram are
uncommon and probably occur only at higher dosages of the drug, which may
result in the inhibition by disulfiram of a variety of enzymes in addition to
aldehyde dehydrogenase. For example, disulfiram inhibits dopamine beta-
hydroxylase, which increases dopamine concentrations, which in turn can
exacerbate psychotic symptoms in patients with schizophrenia and rarely result
in psychotic or depressive symptoms among individuals without a psychotic
disorder. Such symptoms should also lead to discontinuation of the medication.
Disulfiram is administered orally. There is a correlation between the risk of
most adverse effects and dosage, although the risk of hepatic injury does not
appear to be related to dose. This concern about dosage-related adverse events
has resulted in the daily dosage prescribed in the United States being limited to
250-500 mg/d. However, efforts to titrate the dosage of disulfiram in relation to a
challenge dose of ethanol have shown that some patients require in excess of 1
g/d of disulfiram to reach blood levels sufficient to produce a DER (17).
In deciding whether disulfiram should be used in treatment of alcohol use
disorder, patients should be made aware of the hazards of the medication,
including the need to avoid over-the-counter preparations with alcohol and drugs
that can interact with disulfiram and the potential for a DER to be precipitated by
alcohol used in food preparation. The administration of disulfiram to anyone
who does not agree to use it, does not seek to be abstinent from alcohol, has not
attained at least 48 hours of abstinence prior to first administration of disulfiram,
or has any psychological or medical contraindications is not recommended.
Given its potential to produce serious adverse effects when combined with
alcohol, disulfiram cannot be recommended for use as part of a moderation
approach to alcohol treatment.
Medications That Directly Reduce Alcohol

Consumption
Several neurotransmitter systems appear to influence the reinforcing or
discriminative stimulus effects of ethanol: endogenous opioids; catecholamines,
especially dopamine; serotonin (5-HT); and excitatory amino acids (eg,
glutamate) (see references (18) and (19) for detailed reviews of the literature on
the role of these various neurotransmitter systems in alcohol effects). Although
these systems function interactively to influence drinking behavior, many of the
medications that have been employed to treat alcohol use disorder affect
neurotransmitter systems relatively selectively. Consequently, these systems are
discussed individually here.
Opioidergic Agents
Naltrexone and, to a lesser extent, nalmefene, both of which are opioid
antagonists with no intrinsic agonist properties, have been studied for the
treatment of alcohol use disorder. In 1984, naltrexone was approved by the FDA
for the treatment of (pre-DSM-5) opioid dependence; in 1994, it was approved
for the treatment of (pre-DSM-5) alcohol dependence. Nalmefene is approved in
the United States as a parenteral formulation for the acute reversal of opioid
effects (eg, after opioid overdose or analgesia).
Naltrexone
The approval by the FDA of naltrexone for alcohol dependence was based on the
results of two single-site studies, which showed it to be efficacious in the
prevention of relapse to heavy drinking (20,21). In a 12-week trial in a sample of
veterans with alcohol dependence, Volpicelli et al. (20) found naltrexone to be
well tolerated and to result in significantly less craving for alcohol and fewer
drinking days than placebo. Among patients who drank, naltrexone also limited
the progression from initial sampling of alcohol to a relapse to heavy drinking,
presumably because of their experiencing less euphoric effects of alcohol,
suggesting that naltrexone blocked the endogenous opioid system’s contribution
to alcohol’s “priming effect” (22).
The efficacy of combining naltrexone with either supportive or cognitive–
behavioral therapy (CBT) in patients with alcohol dependence was studied by
O’Malley et al. (21). This 12-week trial showed the medication to be well
tolerated and to be superior to placebo in increasing the rate of abstinence and
reducing the number of drinking days and relapse events and the severity of
alcohol-related problems. There was an interaction effect of medication and
therapy. The cumulative rate of abstinence was highest for patients treated with
naltrexone and supportive therapy. However, for patients who drank, those who
received naltrexone and coping skills therapy were least likely to relapse to
heavy drinking.
Analysis of the potential mediating variables in these effects showed that
naltrexone reduced craving for alcohol, alcohol’s reinforcing properties, the
experience of intoxication, and the chances of continued drinking following a
slip (23). During a 6-month, posttreatment follow-up period, the effects of
naltrexone diminished gradually over time, suggesting that patients may benefit
from treatment with naltrexone for longer than 12 weeks (24).
Many, but not all, subsequent studies of naltrexone have provided support
for its use in alcohol treatment. The literature on naltrexone treatment of alcohol
use disorder has been reviewed in detail in a number of meta-analyses (25,26).
The three meta-analyses that included the largest number of studies (26–28)
show a clear advantage for naltrexone over placebo on a number of drinking
outcomes.
Bouza et al. (27) included 19 studies of naltrexone and a total of 3205
participants with alcohol dependence. The large majority of these studies were of
short duration (ie, ≤12 weeks). Using relapse as an outcome, these studies
yielded a highly significant odds ratio (OR) of 0.62 (95% confidence interval
[CI] 0.52 to 0.75), reflecting a 38% lower likelihood of relapse with naltrexone
treatment (p < 0.00001). The likelihood of total abstinence also favored
naltrexone (OR 1.26; 95% CI 0.97 to 1.64), though it did not reach statistical
significance (p = 0.08). Outcomes identified as secondary by this meta-analysis,
including time to relapse, percentage of drinking days, number of drinks per
drinking day, days of abstinence, total alcohol consumption during treatment,
and levels of gamma-glutamyl transpeptidase and aspartate aminotransferase,
also showed a significant advantage for the naltrexone-treated group.
The meta-analysis by Srisurapanont and Jarusuraisin (28) included a total of
2861 subjects from 24 randomized, controlled trials. In the short term,
naltrexone significantly decreased risk of relapse to heavy drinking (relative risk
[RR] 0.64, 95% CI 0.51 to 0.82) but did not reduce the likelihood of a return to
any drinking (RR 0.91, 95% CI 0.81 to 1.02). Treatment with naltrexone
significantly increased adverse effects, roughly doubling the likelihood of
reports of nausea and dizziness and increasing the risk of fatigue by about one-
third compared with placebo. However, naltrexone treatment did not
significantly affect the rate of premature discontinuation of treatment (RR 0.85,
95% CI 0.70 to 1.01).
The meta-analysis of Jonas et al. (26) included 44 placebo-controlled trials
of naltrexone. The number needed to treat to prevent any return to any alcohol
drinking was 20 (95% CI 11 to 500, n = 2347). The number needed to treat to
prevent return to heavy drinking with 50 mg/d oral naltrexone was 12 (95% CI 8
to 26, n = 2875).
Follow-up studies of patients treated with naltrexone or placebo for 12
weeks (24,29) or 4 months (30) have shown that the medication group
differences are no longer significant at posttreatment follow-up. These findings
suggest that treatment with naltrexone is warranted for longer than 4 months,
though the optimal duration of treatment is unknown.
An alternate approach to the use of naltrexone based on its efficacy in
reducing the risk of heavy drinking among patients who continue to drink was
evaluated in a study that compared the effects of naltrexone 50 mg with those of
placebo in an 8-week study of problem drinkers (31). In this study, patients were
randomly assigned to receive study medication either on a daily basis or for use
targeted to situations identified by the patients as being high risk for heavy
drinking (with the number of tablets available for use by patients in the targeted
conditions decreasing over the course of the trial). Irrespective of whether they
received naltrexone or placebo, patients who were trained and encouraged to use
targeted treatment showed a reduced likelihood of any drinking. There was also
a 19% reduction in the likelihood of heavy drinking with naltrexone treatment,
suggesting that naltrexone may be useful in reducing heavy drinking, among
patients who want to reduce their drinking to safe levels.
Targeted naltrexone was also used by Heinala et al. (32), who compared 50
mg/d of the medication with placebo, paired with either coping skills or
supportive therapy. During an initial 12 weeks of treatment, this study showed an
advantage for naltrexone in preventing relapse to heavy drinking but only when
combined with coping skills therapy. During a subsequent 20-week period,
subjects were told to use the medication only when they craved alcohol (ie,
targeted treatment). The beneficial effect of naltrexone on the risk of relapse was
generally sustained during the period of targeted treatment. Based on these
findings, it appears that targeted medication administration may be useful both
for the initial treatment of problem drinking and for maintenance of the
beneficial effects of an initial period of daily naltrexone.
O’Malley et al. (33) conducted a sequence of randomized trials in which
subjects with alcohol dependence were first treated with 10 weeks of open-label
naltrexone 50 mg, combined with either CBT or primary care management
(PCM; a less intensive, supportive approach). Treatment responders from the
PCM group and from the CBT group continued in separate 24-week, placebo-
controlled studies of maintenance naltrexone. No difference was observed with
respect to persistent heavy drinking, with more than 80% of both groups having
a positive outcome. However, the percentage of days abstinent declined more
over time for the PCM group. In the follow-up studies, there was a greater
maintenance response for naltrexone than placebo when combined with PCM,
but the advantage for naltrexone did not reach significance when combined with
CBT. These findings suggest that the beneficial effects of treatment with
naltrexone can be maintained during an extended period through the use of either
a more intensive, skills-oriented treatment (ie, CBT) or a less intensive,
supportive treatment combined with continued naltrexone administration.
Since naltrexone only targets certain aspects of alcohol use disorder (ie,
reduced alcohol reinforcement or cue-induced craving), there has been an
interest in combining it with medications that might influence other
signs/symptoms of alcoholism. Symptoms often seen after alcohol cessation are
difficulty sleeping, anxiety, irritability, decreased concentration, and depressed
mood. This constellation of symptoms has been called protracted withdrawal. If
not addressed, the symptoms of protracted withdrawal are thought to lead to
relapse to alcohol use. The anticonvulsant gabapentin may help reduce these
symptoms. As such, naltrexone has been evaluated in combination with the
anticonvulsant gabapentin to determine if the combination was superior to
naltrexone alone and/or placebo in decreasing alcohol use.
Anton et al. (34) conducted a 16-week clinical trial of 150 subjects with
alcohol dependence who were randomly assigned to naltrexone 50 mg/d alone
for 16 weeks (Heinala = 50), naltrexone 50 mg/d with gabapentin up to 1200
mg/d for the first 6 weeks (Heinala = 50), or double placebo (Heinala = 50). All
study patients received a combined behavioral intervention that combined CBT,
motivation enhancement, and twelve-step facilitation techniques. The results
indicated that during the first 6 weeks, when gabapentin was combined with
naltrexone, the combination group had a longer interval to heavy drinking than
did the naltrexone alone group (which was similar to placebo), had fewer heavy
drinking days than did the naltrexone alone group (which had more than did the
placebo group), and had fewer drinks per drinking day than did the naltrexone
alone group and the placebo group. The findings in the combination group faded
over the remaining weeks of the study. There was some suggestion that the
combination may work best in individuals who had previously experienced
alcohol withdrawal. The investigators hypothesized that the lack of efficacy for
naltrexone versus placebo may have been due to the robust psychosocial
intervention (30).
Poor compliance with oral naltrexone has been shown to reduce the potential
benefits of the medication (35). This has generated interest in the development
and evaluation of long-acting injectable formulations of the medication. The
rationale behind this approach is that monthly, compared with daily,
administration would improve medication adherence and that parenteral
administration would increase bioavailability by avoiding first-pass metabolism.
In addition to the formulations evaluated in published studies, which are
reviewed in the following sections, there are long-acting naltrexone formulations
that are under development for use in the United States, Europe, and Australia.
In a pilot study, patients with alcohol dependence treated with a
subcutaneous depot formulation of naltrexone had detectable plasma
concentrations of the medication for more than 30 days after the injection (36).
In this study, naltrexone was superior to placebo in reducing the frequency of
heavy drinking. Two long-acting naltrexone formulations administered
intramuscularly have also been tested for safety and efficacy in patients with
alcohol dependence. In the first study, naltrexone depot (at a dosage of 300 mg
in the first month and then 150 mg monthly for 2 months) was administered in a
12-week, placebo-controlled trial in 315 patients who also received motivational
enhancement therapy (37). Although naltrexone did not reduce the risk of heavy
drinking, it significantly delayed the onset of any drinking, increased the total
number of abstinent days, and doubled the likelihood of abstinence during the
12-week study period. Two dosage strengths of a second formulation were
evaluated over 6 months of treatment in combination with a low-intensity
psychosocial intervention in more than 600 individuals with alcohol use disorder
who received 6 monthly injections of either long-acting naltrexone (380 mg or
190 mg) or matching volumes of placebo (38). Abstinence from alcohol was not
required for study participation. The medication and the injections were well
tolerated. Compared with placebo, treatment with the 380-mg naltrexone
formulation reduced the event rate of heavy drinking by 25%, a statistically
significant effect. The 17% reduction in the rate of heavy drinking produced by
the 190-mg formulation did not reach statistical significance. On the basis of
these findings, the FDA approved long-acting naltrexone for monthly
administration at a dosage of 380 mg. Because the analysis also showed that the
most robust effects of the medication were seen in patients who were abstinent
(by choice) for at least a week before randomization, the package insert states
that the medication should be used only in individuals with alcohol use disorder
who are abstinent at treatment initiation.
A secondary analysis of data from this study examined efficacy in the
subgroup of 82 patients with 4 days or more of voluntary abstinence before
treatment initiation (39). This shorter period of abstinence made it possible to
include a larger percentage of the study sample in the analysis than was possible
initially with the use of a 7-day interval. In this study, there was a significant
advantage for the 380-mg formulation compared with placebo on a number of
self-report outcome measures, including greater likelihood of total abstinence
(32% vs. 11%), greater median time to a first drinking day (41 days vs. 12 days),
greater median time to a first heavy drinking day (>180 days vs. 20 days), lower
median number of drinking days per month (0.7 vs. 7.2), and lower median
heavy drinking days per month (0.2 days vs. 2.9 days). There was also a
significantly greater improvement in gamma-glutamyl transpeptidase levels in
the 380-mg naltrexone group. Outcomes for the 190-mg group were generally
intermediate between the high-dose and placebo groups.
Based upon hopes for a personalized medicine approach to using naltrexone,
the moderating effect of a polymorphism (A118G or Asn40Asp) in the gene
encoding the μ-opioid receptor on naltrexone treatment response in subjects with
alcohol dependence has been examined with resulting contradictory preliminary
evidence (40,41). However, a rigorous prospective double-blind study that
randomized both on the presence or absence of the polymorphism and to active
naltrexone versus placebo found no evidence of a genotype by treatment
interaction effectively dashing any further considerations of the utility of this
particular personalized medicine approach (19).
Clinical Considerations in the Use of Naltrexone

The clinical use of naltrexone is relatively straightforward, despite the presence
of a “boxed” warning in the label concerning hepatotoxicity for the oral
formulation. The medication should be prescribed at the time that psychosocial
treatment is initiated. Because of adverse effects of the medication that could
compound the adverse effects of alcohol withdrawal, the initiation of naltrexone
therapy is probably best delayed until after the acute withdrawal period. Initial
testing for liver enzyme abnormalities is warranted to avoid prescribing the
medication in the context of extreme elevations. Ongoing monitoring is required
only if symptoms warrant it because the consistent effect of naltrexone in studies
of alcohol use disorder has been to decrease liver enzyme concentrations.
Oral naltrexone should be administered initially at a dosage of 25 mg/d to
minimize adverse effects. The dosage can then be increased in 25-mg increments
every 3-7 days to a maximum dosage of 150 mg/d using desire to drink or
another symptom that the patient identifies as reflective of risk of relapse to
heavy drinking. It should be noted, however, that there is no clear evidence that a
higher dosage is more efficacious than is the FDA-approved dosage of 50 mg/d.
Nausea and other gastrointestinal symptoms are most common early in
treatment, as are neuropsychiatric symptoms (eg, headache, dizziness,
lightheadedness, weakness), and are usually transient. Delaying or avoiding a
dosage increase can be used to address more persistent adverse events. In a few
patients, flu-like symptoms occur, and the patient may not be willing to consider
options other than discontinuation.
Long-acting naltrexone is only available as a 380-mg dose, which should be
administered as a deep intramuscular injection in the upper, outer quadrant of the
gluteal muscle of the buttock every 4 weeks. With repeated administrations, the
injection should be alternated to the side contralateral to the immediately
preceding injection. The medication is approved for use in patients who are
abstinent from alcohol and who are also receiving psychosocial treatment. The
precise length of the period of abstinence is not specified, and there is no
evidence of any risk of consuming alcohol with naltrexone. Adverse effects with
this formulation are similar to those of the oral medication, though pain and
inflammation at the injection site may also occur. Local interventions, such as
warm compresses, and nonsteroidal anti-inflammatory medications can be used
to treat such injection site reactions.
Nalmefene
Nalmefene has also been evaluated as a treatment for alcohol use disorder. As
with naltrexone, nalmefene is an opioid antagonist without agonist properties.
Nalmefene’s affinity for the μ- and κ-opioid receptors is similar to that of
naltrexone, though its affinity for the δ-opioid receptor is greater than that of
naltrexone (42). A pilot study of nalmefene 40 mg/d showed it to be superior to
both 10 mg/d of the medication and placebo in the prevention of relapse to heavy
drinking in patients with alcohol dependence (43). A subsequent study showed
no difference between nalmefene 20 mg/d or 80 mg/d. However, when
combined, the nalmefene-treated subjects reported significantly less heavy
drinking than did the placebo group (44). A 12-week, multisite, dose-ranging
study compared placebo with 5, 20, or 40 mg of nalmefene in a sample of
recently abstinent outpatients with alcohol dependence (45). In this study, all
subjects showed a reduction in self-reported heavy drinking days and on
biological measures of drinking, with no difference between the active
medication and placebo groups on these measures. Recently, targeted nalmefene
(where subjects were encouraged to use 10-40 mg of the medication when they
believed drinking to be imminent) was combined with a minimal psychosocial
intervention in a multicenter, placebo-controlled, randomized trial (46).
Nalmefene was superior to placebo in reducing heavy drinking days, very heavy
drinking days, and drinks per drinking day and in increasing abstinent days.
Further, after 28 weeks of treatment, when a subgroup of nalmefene-treated
subjects was randomized to a withdrawal extension, patients assigned to receive
placebo were more likely to return to heavier drinking. Nalmefene was approved
for reduction of alcohol use by the European Medicines Agency in 2013 at a
dosage of 18 mg/d as needed when the patient perceives a risk of alcohol
consumption.
Summary
There now exists abundant evidence of the efficacy of opioid antagonists
(particularly naltrexone) for the treatment of alcohol use disorder. In unselected
samples of patients, these medications exert a modest overall effect. Targeted
administration of naltrexone and the long-acting injectable formulation may
enhance the clinical utility of this medication. The optimal dosage and duration
of treatment and the relative benefit accruing to combining the medication with
different types and intensities of psychosocial treatment are important clinical
questions that have not yet been adequately addressed.
Acamprosate
Acamprosate (calcium acetyl homotaurinate) is an amino acid derivative that
increases gamma-aminobutyric acid (GABA) neurotransmission and also has
complex effects on excitatory amino acid (ie, glutamate) neurotransmission,
which is most likely the effect that is important for its therapeutic effects in
alcohol use disorder. Acamprosate was first shown in a single-site study to be
twice as effective as placebo in reducing the rate at which patients with alcohol
dependence returned to drinking (47). The medication has been studied
extensively in Europe, and three of the European studies provided the basis for
the approval of acamprosate by the FDA for clinical use in the United States
(48).
Meta-analyses from the European studies provide consistent evidence of the
efficacy of acamprosate in the treatment of alcohol use disorder (26,28,49–51).
The magnitude of the advantage accruing to treatment with acamprosate over
placebo in those studies varied as a function of the outcomes examined but was
in the small range of effect sizes. A meta-analysis of continuous abstinence
showed a significant advantage for acamprosate over placebo, and although the
effects were modest, they increased progressively as treatment duration
increased from 3 to 6 and then to 12 months (50).
Chick et al. (50) sought to determine whether treatment with acamprosate
reduces the severity of relapse for patients in abstinence-oriented treatment who
fail to abstain completely. Among patients who relapsed to drinking,
acamprosate treatment was significantly associated with less quantity and
frequency of drinking than was placebo at follow-up periods as long as 1 year.
Acamprosate also reduced the risk of heavy drinking (ie, 5 or more drinks per
day).
In a study that has implications for the use of acamprosate in combination
with disulfiram, a multicenter trial was conducted in which patients were
randomly assigned to receive acamprosate or placebo, with stratification for
those who voluntarily were using disulfiram. Acamprosate was found to be
superior to placebo on measures of total abstinence and on cumulative abstinent
days (52). The group treated with acamprosate and disulfiram showed a
significantly greater percentage of abstinent days than did any of the other three
groups. However, because the design was not fully randomized, more rigorous
studies of this combination therapy are needed to evaluate the validity of these
findings.
In summary, studies in more than 4000 patients in Europe provide evidence
of a beneficial effect of acamprosate in the prevention of relapse to drinking and
in the reduction of drinking among patients who relapse. Based on the evidence
of its efficacy, the FDA approved the medication for clinical use in the United
States (48). However, two multicenter trials conducted in the United States, the
first being a multicenter trial of two active dosages of acamprosate (53) and the
second being the COMBINE (Combining Medications and Behavioral
Interventions for Alcoholism) study (30), the largest alcohol treatment trial to
date (described in the following section), failed to show an advantage of
acamprosate over placebo on an intent-to-treat basis. This raises the question of
the factors that distinguish alcohol pharmacotherapy trials in Europe from those
in the United States. Differences in features of study design (eg, European
studies required a lengthier period of abstinence) and of the samples studied (eg,
European subjects were heavier drinkers) may explain these discrepant findings.
Clinical Considerations in the Use of Acamprosate

Acamprosate is FDA approved at a dosage of 1998 mg/d (ie, two 333-mg
capsules three times per day) in patients who are abstinent from alcohol and
receiving psychosocial treatment. The most common adverse effects of the drug
are generally mild and transient and include gastrointestinal (eg, diarrhea,
bloating) and dermatological (eg, pruritus) complaints. In contrast to disulfiram
and naltrexone, which are metabolized in the liver, acamprosate is excreted
unmetabolized, so that renal function is the rate-limiting factor in the drug’s
elimination. Evaluation of renal function prior to initiation of the drug is
warranted, particularly in individuals who have a history or are otherwise at risk
of renal disease and in the elderly.
Studies Comparing Acamprosate With
Naltrexone and the Two Medications
Combined
Two placebo-controlled studies have directly compared treatment with
acamprosate, naltrexone, and acamprosate and naltrexone combined. In the first
study, a 12-week trial in 160 patients, all three active medication groups
(naltrexone, acamprosate, and the two medications combined) were significantly
more efficacious than was placebo (54). In that study, although the rate of
relapse of participants in the combined medication group was significantly lower
than that in either the placebo or acamprosate groups, it was not statistically
better than naltrexone alone.
The COMBINE study, a 4-month, multicenter, placebo-controlled study
conducted at 11 sites in the United States, compared naltrexone, acamprosate,
and their combination in a sample of nearly 1400 abstinent alcohol-dependent
subjects. The design of the study was complex, insofar as two different
behavioral interventions (medical management or an intensive behavioral
treatment) were combined with naltrexone (100 mg/d), acamprosate (3 g/d),
naltrexone and acamprosate, or placebo, so that eight groups received study
medication. Further, to evaluate the effects of placebo treatment, a ninth group,
which received an intensive behavioral treatment but no medication, was also
included. Overall, when on study treatment, subjects significantly increased the
percentage of abstinent days. Groups receiving naltrexone and medical
management; intensive behavioral treatment, medical management, and placebo;
and naltrexone, intensive behavioral treatment, and medical management had a
significantly greater percentage of days abstinent than the group receiving
placebo and medical management. Naltrexone also reduced the risk of a heavy
drinking day in the group receiving medical management but not intensive
psychotherapy. In addition to showing a modest advantage for the use of either
naltrexone or intensive behavioral treatment, it is noteworthy that the study
failed to show an advantage for acamprosate over placebo, either alone or when
added to naltrexone on any of the drinking outcomes. The study also showed
evidence of a placebo response among individuals receiving the intensive
behavioral intervention, in that those that received neither an active nor a
placebo medication showed significantly less improvement than those who were
treated with placebo. It should be noted that, with one exception (26), published
meta-analyses do not include data from the COMBINE study, of clear relevance
because it is among the largest studies of either naltrexone or acamprosate.
Anticonvulsants
Of growing interest is the use of anticonvulsants for the treatment of alcohol use
disorder, although currently none are FDA approved for this indication. The
efficacy of this class of medications for the treatment of alcohol use disorder was
initially demonstrated in placebo-controlled studies of carbamazepine (55),
divalproex (56), and topiramate (57), with a multicenter study (58) confirming
the efficacy of topiramate for this indication. Although these medications have
different mechanisms of action, it is likely that they exert beneficial effects in
alcohol use disorder through their actions as glutamate antagonists and GABA
agonists, helping to normalize the abnormal activity in these neurotransmitter
systems seen following chronic heavy drinking.
In a 12-month pilot study, Mueller et al. (55) found carbamazepine to be
superior to placebo in increasing the time to the first heavy drinking day and in
reducing drinks/drinking day and the number of consecutive days of heavy
drinking. In a 12-week, double-blind pilot study, Brady et al. (56) found that a
significantly lower percentage of patients receiving divalproex than placebo
relapsed to heavy drinking. There was also a significantly greater decrease in
irritability in the divalproex-treated group.
Johnson et al. (57) initially conducted a single-site, 12-week, placebo-
controlled study of topiramate, with the dosage gradually increased over 8 weeks
to a maximum of 300 mg. Topiramate-treated patients showed significantly
greater reductions than did placebo-treated patients in drinks per day, drinks per
drinking day, drinking days, heavy drinking days, and γ-glutamyl transpeptidase
levels. Based on these findings, a subsequent multicenter study was conducted
(58), which showed many of the same effects on drinking as the single-site
study, though topiramate was not as well tolerated as it was in the initial trial.
The authors interpreted these findings to reflect the more rapid dose titration (to
a maximum of 300 mg, but over 6 weeks).
The most common adverse effect of topiramate compared to placebo is
numbness and tingling (which is secondary to the commonly observed metabolic
acidosis produced by the antagonism by topiramate of carbonic anhydrase), with
other common side effects including a change in the sense of taste,
tiredness/sleepiness, fatigue, dizziness, loss of appetite, nausea, diarrhea, weight
decrease, and difficulty concentrating, with memory, and in word finding. Of
clinical concern also are suicidal thoughts or actions, which have been reported
uncommonly but at a frequency greater than that seen with placebo treatment.
Other adverse effects of topiramate that are less likely to occur but potentially
serious are renal calculi and acute secondary glaucoma.
These findings provide clear support for the efficacy of this anticonvulsant
for the treatment of alcohol use disorder and suggest that the use of topiramate
for this purpose should include a slowly increasing dosage. Additional research
focusing on the optimal rate of dosage increase and the minimal dosage that is
efficacious in alcohol use disorder is warranted. In regard to personalized
medicine, a randomized, controlled, double-blind trial of topiramate 200 mg/d
versus placebo showed a robust effect of topiramate on number of heavy
drinking days, but in a subsample of European Americans, this effect was
accounted for almost entirely by a single nucleotide polymorphism in the gene
coding for one of the subunits of the kainate type of glutamate receptor (59).
This finding requires replication in a larger prospective study before it would be
clinically applicable.
Mason and colleagues (60) conducted a 12-week, double-blind trial (n =
150) of two different doses of gabapentin (900 mg, 1800 mg) versus placebo in
patients with alcohol dependence. Significant linear dose effects were reported
with abstinence rate, no heavy drinking, cravings, mood and sleep. These effects
were more pronounced in the gabapentin 1800 mg group (abstinence: NNT = 8;
no heavy drinking: NNT 5). These finding add to the literature suggesting
gabapentin may reduce heavy drinking, increase abstinence, improve sleep, and
reduce acute/protracted withdrawal syndromes (61,62). Larger trials are
warranted.
Baclofen
This GABA-B receptor agonist has been approved as an antispasmodic for more
than 30 years and has recently been studied as a treatment for alcohol use
disorder, although not FDA approved for such treatment. In a small trial,
Addolorato et al. (63) randomly assigned recently abstinent individuals with
alcohol dependence to receive up to 30 mg/d of the medication or placebo
divided into three daily doses. The medication was well tolerated, and the
baclofen-treated group was more likely to remain abstinent over the 1-month
treatment period (also showing a greater number of cumulative abstinence days)
than was the placebo group. More recently, these investigators (64) evaluated the
efficacy of baclofen in a sample of 84 patients with alcohol dependence with
liver cirrhosis. Baclofen-treated patients were significantly more likely than were
placebo-treated patients to maintain abstinence (71% vs. 29%), with a
concomitant doubling of abstinence days in the baclofen group. The medication
was well tolerated, and the baclofen group showed a nonsignificantly lower rate
of study dropout than did the placebo group (14% vs. 31%).
More recent studies have shown contradictory findings. A flexible dosing
double-blind randomized trial with 56 participants found significantly higher
total abstinence rates and abstinence duration among participant who received
active medication (mean dose in the active baclofen group = 180 mg [SD =
86.9]/day) (65). However, a larger multicenter randomized, double-blind trial
with 151 participants compared a high-dose baclofen group (mean = 93.6 [SD =
40.3]/day) to 30 mg/d and placebo groups and saw no differences between
groups in any measure of alcohol use while also noting frequent adverse events
in the high-dose group (66). Another multicenter randomized, double-blind trial
among 180 U.S. military Veterans similarly found no effect of baclofen 30 mg/d
compared to placebo on any alcohol use outcomes (67). Overall, there is
insufficient evidence for efficacy of baclofen in treatment of alcohol use disorder
at the present time.
Serotonergic Agents in Alcohol Use Disorder

Subtypes
Although there is no evidence overall that serotonergic agents act as effective
treatments for alcohol use disorder, they may have benefit in certain subtypes.
Adapting an approach first used by Kranzler et al. (68), Pettinati et al. (69) found
that low-risk/low-severity patients with alcohol dependence (ie, those with later
age of onset) drank on fewer days and were more likely to be completely
abstinent in the 12-week treatment trial when treated with sertraline compared
with placebo. In a 6-month posttreatment follow-up of these patients (70), the
beneficial effects of sertraline treatment persisted in this subgroup. Chick et al.
(71) also found an effect with fluvoxamine that was similar to that observed with
fluoxetine (68). Specifically, among early-onset drinkers, fluvoxamine was
associated with worse outcome than placebo.
Using a subtyping approach, Johnson et al. (72) found that ondansetron (a 5-
HT receptor antagonist) selectively reduced drinking among patients with early
onset of problem drinking (ie, before age 25; early-onset patients with alcohol
dependence). Specifically, ondansetron was superior to placebo on the
proportion of days abstinent and on the intensity of alcohol intake. In contrast,
late-onset patients with alcohol dependence showed effects of ondansetron on
drinking behavior that were comparable to those of placebo. In a subsequent 8-
week, open-label study of ondansetron, early-onset patients with alcohol
dependence had a significantly greater decrease in drinks per day, drinks per
drinking day, and alcohol-related problems than did late-onset patients with
alcohol dependence (73). Furthermore, a prospective double-blind trial of
ondansetron in which participants were randomized based upon polymorphisms
in the gene coding for the serotonin transporter showed a positive response in
participants with the polymorphisms (74). A retrospective analysis of the same
data showed that polymorphisms in the genes coding for serotonin 5-HT3
receptor subtypes also predicted outcome (75). Additional prospective and
replication studies are needed to evaluate whether there is a clearer role for the
serotonergic medications in the treatment of heavy drinking or alcohol use
disorder in individuals differentiated by alcohol use disorder subtype or
genotype.
MEDICATIONS TO TREAT CO-

OCCURRING PSYCHIATRIC
SYMPTOMS OR DISORDERS IN
PATIENTS WITH ALCOHOL USE
DISORDER
Although most patients with alcohol use disorders report a reduction in mood or
anxiety symptoms following acute withdrawal, for some, these symptoms may
persist for months. Even among patients without substantial symptoms of
alcohol withdrawal, persistent, low-level mood or anxiety symptoms may
develop, a condition that has been called “subacute withdrawal.” In a substantial
minority of patients, these symptoms may reflect diagnosable psychiatric
disorders. Although medications (eg, serotonin reuptake inhibitors) are often
prescribed during the postwithdrawal period in hopes of relieving these
symptoms, there is not good evidence that the treatment of persistent or subacute
withdrawal symptoms that do not meet diagnostic criteria for a co-occurring
psychiatric disorder results in better outcome in patients with alcohol use
disorder.
Many of the early studies of the efficacy of medications to treat mood
disturbances targeted symptoms of depression and anxiety in unselected groups
of patients with alcohol use disorder after withdrawal. These and other
methodological limitations in these studies make the failure to demonstrate an
advantage over control conditions through reductions in either psychiatric
symptoms or drinking behavior difficult to interpret (76). Over the past 10-15
years, there has been renewed interest in the incidence and prevalence of co-
occurring psychiatric disturbances among patients with alcohol use disorder
(77). Community studies have shown high rates of co-occurrence of psychiatric
disorders in individuals with alcohol use disorder (78,79). Further, the majority
of such individuals who seek treatment meet lifetime criteria for one or more
psychiatric disorders in addition to alcohol use disorder, most commonly mood
disorders, drug dependence, antisocial personality disorder, and anxiety
disorders (80,81).
Antidepressants, benzodiazepines and other anxiolytics, antipsychotics, and
lithium have been used to treat anxiety and depression in the postwithdrawal
state. Although, in general, the indications for use of these medications in
patients with alcohol use disorder are similar to those for patients with
psychiatric illness who do not have alcohol use disorder, careful differential
diagnosis is warranted to identify patients for whom the symptoms can be
ascribed to substance use. Further, the choice of medications should take into
account the increased potential for adverse effects when prescribed to
individuals who are actively drinking heavily. Adverse effects can result from
pharmacodynamic interactions with medical disorders that commonly occur in
the course of alcohol use disorder, as well as from pharmacokinetic interactions
with medications prescribed to treat these disorders (82).
Antidepressant Treatment of Unipolar

Depression and Alcohol Use Disorder
A majority of the studies in a meta-analysis that included 14 prospective,
parallel-group, double-blind, randomized, placebo-controlled trials of
antidepressants for a co-occurring substance use disorder and unipolar
depression focused on alcohol dependence (83). Eight studies (six of which were
in patients with alcohol dependence) showed a significant or near-significant
advantage for the active medication over placebo in reducing symptoms of
depression. The pooled effect size on the standardized difference between means
on the Hamilton Depression Rating Scale was 0.38 (95% CI 0.18 to 0.58), a
small to moderate effect. Studies with a placebo response rate > 25% showed no
advantage for the active medication, whereas those with a smaller placebo
response rate yielded effects in the moderate to large range. Allowing a week of
abstinence to transpire before making a diagnosis of depression predicted a
better antidepressant response. In contrast, a larger proportion of women in the
study sample, the use of serotonin reuptake inhibitors (vs. tricyclic or other
antidepressants), and a concurrent psychosocial intervention were associated
with a poorer medication response. Studies that showed a moderate effect of the
medication on depression scores also showed moderate reductions in substance
use, whereas smaller effects on depressive symptoms were associated with no
beneficial effects on substance use.
Subsequent to the analysis by Nunes and Levin (83), there have been studies
of pharmacotherapy for co-occurring alcohol dependence and depression.
Hernandez-Avila et al. (84) compared nefazodone with placebo in subjects with
alcohol dependence with current major depression. Although there were greater
reductions in anxiety and depressive symptoms in the nefazodone group, the
effects did not reach statistical significance, potentially because of the small
sample size. Nonetheless, nefazodone-treated subjects reduced the frequency of
heavy drinking days and total number of drinks more than did placebo-treated
subjects. The occurrence of a limited number of reported cases of idiosyncratic
hepatic failure during nefazodone treatment limits the drug’s clinical utility.
Kranzler et al. (85) conducted a multicenter trial of sertraline in 328 patients
with co-occurring major depressive disorder and alcohol dependence. After a 1-
week, single-blind, placebo lead-in period, patients were randomly assigned to
receive 10 weeks of treatment with sertraline or placebo. Randomization was
stratified, based on whether initially elevated depression scores declined with the
cessation of heavy drinking. Both depressive symptoms and alcohol
consumption decreased substantially over time in both groups, with no reliable
medication group differences on depressive symptoms or drinking behavior in
either group. The high placebo response rate may have contributed to the null
findings.
Pettinati et al. (86) performed an elegant clinical trial in which participants
with co-occurring major depression and alcohol dependence were randomly
assigned in double-blind fashion to one of four treatment conditions: (a)
sertraline 200 mg/d (n = 40), (b) naltrexone 100 mg/d (n = 49), (c) the
combination of sertraline 200 mg/d and naltrexone 100 mg/d (n = 42), and (d)
double placebo (n = 39). Over 14 weeks, the combination treatment group had a
significantly higher abstinence rate and a significantly longer mean time to
relapse to heavy drinking than did the other three groups. The combination
group also had higher, though not statistically significantly higher, rates of
depression remission with fewer serious adverse events than did the other three
groups. The impressive findings from this study, absent any contraindications,
strongly encourage the combination of naltrexone and sertraline for the treatment
of patients with co-occurring alcohol use disorder and depression.
In summary, there is evidence that most episodes of postwithdrawal
depression will remit without specific treatment if abstinence from alcohol is
maintained for a period of days or weeks (87,88). However, persistent depression
requires treatment. Serotonin reuptake inhibitors and newer generation
antidepressants have become the first-line treatment of depression because they
have a favorable adverse event profile. These medications do not have the
anticholinergic, hypotensive, or sedative effects of the tricyclic antidepressants,
nor do they, with the possible exception of citalopram, have the adverse
cardiovascular effects, which in overdose can be lethal. However, serotonin
reuptake inhibitors can exacerbate the tremor, anxiety, and insomnia often
experienced by patients with physiological dependence on alcohol who have
been recently withdrawn from alcohol and may slightly increase the risk of
gastrointestinal bleeding (particularly in combination with nonsteroidal anti-
inflammatory drugs or aspirin). Furthermore, the findings of Nunes and Levin
(83) suggest that for the treatment of depression among patients with a substance
use disorder, serotonin reuptake inhibitors may be less efficacious than tricyclic
or other types of antidepressants.
Mood Stabilizer Treatment of Bipolar

Disorder and Alcohol Use Disorder
Bipolar disorder co-occurs commonly with alcohol use disorder. The presence of
comorbid alcohol use disorder is associated with an increased rate of mixed or
dysphoric mania and rapid cycling, as well as greater bipolar symptom severity,
suicidality, and aggression (89). However, controlled trials of medication to treat
these comorbid disorders are difficult to conduct. A placebo-controlled trial of
divalproex sodium in bipolar patients with DSM-IV alcohol dependence taking
lithium showed that the drug significantly decreased the proportion of heavy
drinking days (corroborated by a decrease in the concentration of gamma-
glutamyl transpeptidase), whereas manic and depressive symptoms improved
equally in both groups (90).
Treatment of Co-occurring Anxiety Disorders
and Alcohol Use Disorder
Benzodiazepines and Other Anxiolytics
Benzodiazepines are widely used and generally considered to be acceptable
treatment for acute alcohol withdrawal. In contrast, most nonmedical personnel
involved in the treatment of alcohol use disorder oppose the use of medications
that can induce physical dependence or even a substance use disorder, to treat the
anxiety, depression, and sleep disturbances that can persist for months after
withdrawal. The relative merits of the use of benzodiazepines in patients with
alcohol and other substance use disorders during the postwithdrawal period for
the management of anxiety or insomnia have also been debated in the medical
literature (91,92).
Despite the risks that the use of benzodiazepines may create in patients with
alcohol use disorder beyond the period of acute withdrawal (eg, physical
dependence or overdose), judicious use of the drugs in this setting may be
justified. Early relapse, which commonly disrupts alcohol rehabilitation, can
result from protracted withdrawal-related symptoms (eg, anxiety, depression,
insomnia). To the extent that these symptoms can be suppressed by low doses of
benzodiazepines, retention in treatment could be increased (93). Moreover, for
some patients, benzodiazepine use disorder, if it does occur, may be more benign
than alcohol use disorder.
The controversy surrounding this approach to alcohol treatment stems from
the fact that these potential benefits must be weighed against the risk both of
overdose and of physical dependence on benzodiazepines. Although these drugs
alone are comparatively safe, even in overdose, their combination with other
brain depressants (including alcohol) can be lethal. Although there is little doubt
that individuals with alcohol use disorder are more vulnerable to develop
dependence on the benzodiazepines than is the average person, the potential for
developing a use disorder may be lower than is generally believed (94,95).
However, physiological dependence on both alcohol and benzodiazepines may
increase depressive symptoms (87), and co-occurring alcohol and
benzodiazepine use disorders may be more difficult to treat than is alcohol use
disorder alone (96).
The benzodiazepines currently available for clinical use vary by
pharmacokinetics, in their acute euphoric effects, and the frequency with which
they are reported to cause physiological dependence. Diazepam, lorazepam, and
alprazolam may have greater potential for a substance use disorder than does
chlordiazepoxide or clorazepate (97). Similarly, oxazepam was reported to
produce low levels of nonmedical use (94). Jaffe et al. (98) found that, when
administered to recently withdrawn patients with alcohol dependence,
halazepam produces minimal euphoria even at a supratherapeutic dosage. Partial
agonist compounds at the benzodiazepine receptor complex may offer an
advantage over approved benzodiazepines for use in individuals with alcohol use
disorder, though there is no literature as yet that addresses this question.
Buspirone, a nonbenzodiazepine anxiolytic, exerts its effects largely via its
partial agonist activity at serotonergic autoreceptors. Although comparable in
efficacy to diazepam in the relief of anxiety and associated depression in
outpatients with moderate-to-severe anxiety (99,100), buspirone is less sedating
than is diazepam or clorazepate, does not interact with alcohol to impair
psychomotor skills, and does not have substance use disorder liability (101,102).
This pharmacological profile makes buspirone more suitable than
benzodiazepines to treat anxiety symptoms among patients with alcohol
dependence. In contrast to benzodiazepines, however, buspirone does not have
acute anxiolytic effects, is not useful in the treatment of alcohol withdrawal, and
is not useful for treating the insomnia that is commonly reported by patients with
alcohol use disorder during acute and protracted withdrawal.
Results from three of four placebo-controlled, double-blind trials of
buspirone to treat anxiety symptoms among patients with alcohol use disorder
have shown the drug to be superior to placebo in increasing treatment retention
and reducing anxiety symptoms and measures of drinking (103,104). Although
buspirone appears to be useful in the treatment of anxiety symptoms in patients
with alcohol use disorder, it has not been possible to identify clinical features
that differentiate individuals for whom buspirone may be most efficacious from
those who are not responsive to the medication.
THE USE OF PHARMACOTHERAPIES IN

THE TREATMENT OF ALCOHOL USE
DISORDER
Despite data suggesting efficacy, the use of medications that have been approved
for treatment of alcohol use disorder remains very limited. The lack of robust
utilization can be found in large organizations such as the Veterans Health
Administration as well as other public and private entities (105,106). This
limited use is evident even in clinicians who have been trained to treat alcohol
use disorder—addiction physicians. A survey of nearly 1400 members of the
American Society of Addiction Medicine and the American Academy of
Addiction Psychiatry (107) showed that they prescribed disulfiram to only 9% of
their patients with alcohol dependence, and naltrexone was prescribed only
slightly more frequently (ie, to 13% of patients). In contrast, antidepressants
were prescribed to 44% of patients with alcohol use disorder. Although nearly all
of these physicians had heard of disulfiram and naltrexone, their self-reported
level of knowledge of these medications was much lower than that for
antidepressants and benzodiazepines. Additionally, primary care physicians,
which represent the clinicians most likely to diagnose alcohol use disorder, were
found in the not too distant past to be unfamiliar with approved
pharmacotherapies (108). Clearly, additional education is needed to improve
awareness among treatment professionals as well as patients.
SUMMARY AND CONCLUSIONS

Although continuing developments in the United States, Europe, and Australia
suggest that medications may eventually become a key element in alcohol
treatment, many clinical questions must be considered before medications are
likely to be widely employed for this indication. In addition to the issues
discussed earlier in regard to specific agents (eg, What is the optimal duration of
naltrexone treatment?), the safety and efficacy of medications to treat alcohol
use disorder must be examined with adequate statistical power in women, in
different ethnic/racial groups, and in adolescent and geriatric samples.
The treatment of psychiatric symptoms that co-occur with alcohol use
disorder, which can augment efforts at relapse prevention, has been studied in
some detail (76). However, the literature remains mixed with respect to the
efficacy of specific interventions. Anxiolytics that are low in nonmedical
potential, such as buspirone, and antidepressants with benign side effect profiles,
such as the newer generation drugs that may reduce ethanol intake, warrant
careful evaluation in the treatment of anxious and depressed patients with
alcohol use disorder.
However, even if medications that are prescribed to patients with alcohol use
disorder with persistent co-occurring mood and anxiety symptoms ameliorate
those symptoms, they will not necessarily reduce alcohol consumption after a
significant degree of alcohol use disorder develops. This is likely to hold true
even if pathological mood states were important in the initiation of heavy
drinking (77,109). That is, the neuroadaptive changes and the complex learning
that characterize alcohol use disorder (110) are not likely to resolve because one
major contributing factor is brought under control. The challenge for
practitioners treating alcohol use disorder is to combine efficacious medications
with empirically based psychological interventions and self-help group
participation for those patients willing and able to incorporate these elements
into their treatment.
The medications that have been most widely studied in alcohol treatment are
disulfiram, naltrexone, and acamprosate. Results from the COMBINE study and
trials of depot naltrexone formulations, topiramate, and gabapentin have
provided important new information on the use of these medications in alcohol
treatment. As the research literature on the use of medications to treat alcohol
use disorder grows, it will be possible to assess the utility of different medication
combinations and a variety of psychotherapies. There are also ongoing efforts to
match medications with specific subgroups of patients with alcohol use disorder,
based on clinical or genetic characteristics, and these are beginning to bear fruit.
The use of medications in patients who are actively participating in self-help
groups may be particularly challenging. Although members of abstinence-
oriented groups such as Alcoholics Anonymous may be willing to work with
physicians when they prescribe disulfiram, the use of which is supportive of
their goal of total abstinence, they may be less supportive of other medications
that aim to reduce drinking and its associated medical, psychological, and social
harm.
As evidence has accumulated showing that a growing number of
medications are efficacious for the treatment of alcohol use disorder, the
therapeutic options available to physicians in treating these patients have
increased. Nonetheless, many of these developments have not been translated to
widespread changes in treatment. The major challenge to medications
development will be to identify new medications that are efficacious and well
tolerated, as well as the patient and treatment factors that can be used to optimize
effectiveness. Because all three medications that are FDA approved for the
treatment of alcohol use disorder have demonstrated efficacy in some patients,
these medications should be considered a first-line treatment in patients with
alcohol use disorder, to be used in combination with behavioral treatment. Given
limited data on how to choose which of the efficacious medications is
appropriate for any given patient, the choice can be made based on physician and
patient preference.
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CHAPTER 56
Pharmacological Interventions for
Sedative–Hypnotic Use Disorder
Jeffrey S. Cluver, Tara M. Wright and Hugh Myrick
CHAPTER OUTLINE
Introduction
Pharmacology
Definitions
Use of Sedative–Hypnotic Medications
Indications for Pharmacological Interventions
Management of Intoxication and Overdose
Withdrawal
Management of Withdrawal
Treatment Setting
Treatment of Co-occurring Disorders
Conclusions and Future Directions
INTRODUCTION
Sedative–hypnotic agents have long been popular in medicine because of their
ability to mitigate anxiety and induce sleep. Most of the drugs in this class of
medications have a mechanism of action in the central nervous system (CNS)
that leads to their anxiolytic and sleep-inducing properties. Prior to 1900, agents
such as chloral hydrate, bromide, paraldehyde, and sulfur were used. The first
barbiturate (barbital, a derivative of barbituric acid) was introduced in 1903 and
soon became popular because of its predictable ability to induce sleep and
decrease anxiety. Phenobarbital was introduced in 1912, and in addition to the
effects seen with barbital, this medication was also shown to have anticonvulsant
properties. Despite safety and non-medical use issues, such as its narrow
therapeutic index, tolerance, and drug interactions, phenobarbital proved to be a
popular medication, and thousands of derivative compounds were developed.
While there are still a number of barbiturates available, their clinical use has
been largely supplanted by benzodiazepines.
The first benzodiazepine was synthesized in 1957. Chlordiazepoxide
(Librium) and the other benzodiazepines that followed, were found to be useful
in the treatment of anxiety and sleep disorders. While the properties of
benzodiazepines and barbiturates are similar, the relative safety and tolerability
of the benzodiazepines has led to their widespread and lasting use. Medications
in the benzodiazepine class all share a similar structure and bind to the same
receptor site on the gamma-aminobutyric acid (GABA) receptor.
Barbiturates also act on the GABA receptor, by binding to a different subunit
than the benzodiazepines. Other relatively new additions to this category of
medications are the imidazopyridine derivatives (zolpidem and others), zaleplon,
and eszopiclone. These medications are chemically distinct from
benzodiazepines, but they also bind to the GABA receptor, at the omega subunit.
In Table 56-1, currently available sedative–hypnotic agents are listed. It has
been reported that the behavioral and subjective effects (including subject-rated
measures related to addiction potential) of the newer compounds (zolpidem,
zaleplon, and eszopiclone) are similar to those of the traditional
benzodiazepines, in both individuals with and without a history of substance use
disorders (1,2), and self-administration in laboratory animals has also been seen
(3). Benzodiazepines and other sedative–hypnotics lend themselves to misuse,
including use in conjunction with other substances (4). These medications can be
used to enhance the effects of the other substances, or to help an individual cope
with unpleasant side effects of other drug use or withdrawal. Additionally, alone
or when used with other CNS depressants, benzodiazepines and sedative–
hypnotics can lead to respiratory depression, coma, and death. In this chapter, we
focus on the management of individuals with sedative, hypnotic, or anxiolytic
use disorder, especially in the context of withdrawal.
TABLE 56-1 Classes of Sedative–Hypnotic Drugs: Drug

Classes, Nonproprietary Names, and Trade Names
PHARMACOLOGY
As mentioned previously, the effects of benzodiazepines and other sedative–
hypnotics are mediated by their binding to the GABA receptor. GABA receptors
are distributed widely throughout the brain and are so named because they bind
GABA, the major inhibitory neurotransmitter in the CNS. There are specific
receptor subunits that are allosterically bound to the GABA receptor, and these
medications act as agonists by increasing the ability of the inhibitory
neurotransmitter GABA to bind to and activate the GABA-A receptor. When an
agonist such as a benzodiazepine or barbiturate binds to the GABA receptor, the
receptor opens its chloride channel, which then decreases neuronal excitability.
Clinically, this leads to the effects of decreased anxiety, increased sedation,
muscle relaxation, and increased seizure threshold. The toxic effects of these
compounds are caused by excessive opening of chloride channels and can lead to
respiratory depression. Barbiturates increase GABA-A activity by increasing the
duration of chloride channel opening, which can lead to excessive activity of
GABA-A receptor and respiratory depression. Benzodiazepines affect GABA-A
activity by increasing the frequency of chloride channel opening, which can also
lead to toxicity, but with a larger therapeutic index. The imidazopyridine
derivatives zolpidem and zaleplon bind with high affinity at the type I
benzodiazepine recognition site, on the GABA-A receptor omega subunit.
Among the sedative–hypnotic agents, there are important differences in the onset
of activity, half-life of the medication, presence of active metabolites, and
specificity of the clinical effects.
While benzodiazepines and other sedative–hypnotics are agonists at the
GABA receptor, there are also inverse agonists (such as beta-carboline) that bind
to the GABA receptor but cause the chloride channels to close. Such inverse
agonists can cause increased anxiety and lower the seizure threshold. Flumazenil
is an antagonist compound with a high affinity for the GABA receptor. This
medication was developed and marketed to reverse the effects of
benzodiazepines, including sedation and respiratory depression.
DEFINITIONS
It is worth taking a moment to clarify several definitions, especially when
discussing this class of medications. Physical dependence can be defined as an
altered homeostasis at several levels of drug effect and activity. Examples of
physical dependence include tolerance and withdrawal. Discontinuation of the
drug in this state leads to symptoms resulting from a disruption of this
homeostasis. Tolerance can be defined as a decreased pharmacological effect
after repeated or prolonged exposure to the drug so that higher doses are needed
to achieve the same initial clinical effects. Both physical dependence and
tolerance are inevitable with prolonged and regular use of medications in the
class of benzodiazepines and other sedative–hypnotics. Non-medical use
generally refers to inappropriate use of a medication such as the use of a higher
dose than prescribed. Substance use disorder is defined by the Diagnostic and
Statistical Manual of Mental Disorders (DSM-5) criteria as a maladaptive pattern
of substance use leading to clinically significant impairment or distress, defined
by meeting multiple specified criteria within a 12-month period. Drugs with
reinforcing properties, such as the ability to produce euphoria, reduce unpleasant
sensations, or induce other positive subjective experiences, are more likely to
lead to a substance use disorder. The onset of physical dependence should not be
equated with, or imply, the presence of a substance use disorder, although the
two often coexist. Similarly, the misuse of a medication does not directly imply a
substance use disorder, as may be the case in patients with severe anxiety
disorders who do not achieve relief with their initially prescribed doses.
USE OF SEDATIVE–HYPNOTIC
MEDICATIONS
Benzodiazepines have largely replaced barbiturates and other sedative–hypnotics
in clinical settings, due to their preferred pharmacological profile. According to
IMS Health, there were 49.0 million alprazolam, 27.6 million lorazepam, 26.9
million clonazepam, 15.0 million diazepam, and 8.5 million temazepam
prescriptions dispensed in the USA in 2011 (5).
An estimated 1.9 million people aged 12 or older in 2015 reported non-
medical use of tranquilizers, and an estimated 446 000 people aged 12 or older
reported non-medical use of sedatives in** 2015 (6). These medications are
often initially prescribed for the treatment of anxiety disorders and insomnia, but
their non-medical use (use at high doses or more frequent intervals) often leads
to euphoria and disinhibition.
Laboratory studies involving rats and nonhuman primates demonstrate that
many sedative–hypnotics are self-administered, although the benzodiazepines
appear to be less reinforcing than barbiturates (7). While there have been human
studies that have demonstrated the reinforcing effects of the benzodiazepines,
there are notable differences among the compounds, which correlate with the
agents’ onset of action. Lorazepam, alprazolam, and diazepam all appear to have
a greater potential for non-medical use, likely based on their inherent lipophilic
properties, and therefore more rapid onset of action. It is also important to note
that other human studies have demonstrated that benzodiazepines do not have
reinforcing effects in a majority of individuals (8), thus suggesting that some
individuals may have a vulnerability that leads to non-medical use.
The non-medical use of benzodiazepines and sedative–hypnotics is
commonly seen in individuals with other substance use disorders (9). In this
context, sedative–hypnotics are often used to enhance the effects of other drugs
and alleviate unpleasant side effects from use or withdrawal of other substances.
Benzodiazepines and other sedative–hypnotics may also be used when
individuals who use many substances cannot obtain their substance of choice.
Many patients who develop benzodiazepine and sedative–hypnotic use disorders
were initially being treated for problems with sleep and anxiety disorders.
Individuals seeking treatment for anxiety disorders, sleep disorders, and
depression are at higher risk for developing sedative–hypnotic use disorder if
they have a history of substance use disorders. A family history of substance use
disorders also places an individual at higher risk for developing a substance use
disorder. The issue of alcohol use disorder warrants special caution because of
the potential for dangerous interactions. The assumption that all individuals with
alcohol use disorder have a propensity for non-medical use of benzodiazepines
or invariably developing a use disorder has been challenged (10), but the use of
these medications should be closely monitored in this population.
INDICATIONS FOR
PHARMACOLOGICAL INTERVENTIONS
In general, there are two clear indications for pharmacological intervention in
individuals who are taking benzodiazepines and other sedative–hypnotics. In a
state of intoxication, a patient may require monitoring and even intervention to
ensure a safe recovery. In patients experiencing acute withdrawal,
pharmacological management is often recommended because of the risk of
dangerous sequelae, including seizures and sedative withdrawal delirium.
Deciding whether or not a benzodiazepine or other sedative–hypnotic should be
used on a long-term basis is important to consider early on in the treatment
course. In general, if there is a clear diagnosis, benefit from the treatment,
minimal side effects, and no evidence of non-medical use or substance use
disorder, then the medication could be continued (11). Sedative–hypnotics are
commonly recommended for the shortest period of time possible, and these
medications are often seen as short-term therapies that should be discontinued as
soon as the clinical situation permits. The American Psychiatric Association
published guidelines in a 1991 task force report (12), and while these have not
been updated, there continues to be increased scrutiny on the effectiveness of
these medications, especially in long-term use, and in the elderly (13,14).
MANAGEMENT OF INTOXICATION
AND OVERDOSE
The signs and symptoms of benzodiazepine and sedative–hypnotic intoxication
are very similar to those of alcohol intoxication. Severe intoxication can lead to
respiratory depression, coma, and death. Benzodiazepine intoxication, even in
the context of intentional overdose, rarely leads to death, unless the
benzodiazepines are combined with other CNS depressants. The management of
acute intoxication is mostly supportive, with special attention to airway
management, as respiratory depression is the most likely cause of death in
overdose. In overdose, it is also critical to know what other psychoactive agents
(especially CNS depressants) may have been acutely or chronically ingested.
Flumazenil can be used in the case of benzodiazepine intoxication and
overdose, but its use is limited by the risk of precipitating withdrawal symptoms,
including seizures, if this is not used with caution. Flumazenil can be considered
in patients who have confirmed or suspected benzodiazepine toxicity, who have
lost consciousness or are at risk of losing consciousness, and who may require
intubation. Flumazenil should be avoided in patients who have also recently
ingested medications or substances that lower the seizure threshold, in patients
with known or suspected epilepsy, and in patients who have developed
physiological dependence on benzodiazepines. Because of the risk of adverse
events related to the administration of flumazenil, it should be administered in
the lowest possible doses for the shortest period of time required and in a
medical setting where resuscitation equipment and appropriately trained health
care personnel are present (15–18).
WITHDRAWAL
Withdrawal symptoms are most often seen in patients with physiological
dependence after abruptly discontinuing benzodiazepines or other sedative–
hypnotics (19). Withdrawal may be precipitated unintentionally when an
individual stops taking a prescribed medication or is unable to obtain the
sedative–hypnotic from illicit sources. Withdrawal may also be inadvertently
initiated by a provider due to concerns of misuse, psychological dependence, or
other substance use disorders. In some cases, the decision is made to stop
benzodiazepines because of side effects, such as memory impairment or
behavioral problems. Individuals are more likely to develop withdrawal
symptoms when they have been taking high doses of sedative–hypnotics, and if
they have been taking even low or moderate doses for a prolonged period of time
(7,20).
While withdrawal symptoms are similar to those seen in alcohol withdrawal
(Table 56-2), the signs and symptoms of withdrawal manifest in a somewhat
idiosyncratic manner in each patient. Individual traits such as age and medical
conditions and the unique pharmacological properties of each medication (21) all
impact the types and severity of the withdrawal symptoms that are experienced.
The onset and duration of withdrawal symptoms depend on the intrinsic
pharmacokinetic properties (ie, half-life) of the agent itself as well as extrinsic
factors that impact the metabolism and effective half-life of the agent, such as
the inhibition or induction of cytochrome P-450 enzymes, patient age, and
preexisting liver disease. The half-life of the medication, and its active
metabolites, is of particular importance, especially when discussing the onset of
withdrawal symptoms. Withdrawal from medications with short half-lives
usually begins within 12-24 hours, and reaches peak intensity within 1-3 days.
With longer-acting agents, withdrawal symptoms may begin later and not peak
until 4-7 days after discontinuation. Symptoms may then continue for several
more days or even weeks, depending on the half-life of drug. Advanced liver
disease may lead to significantly prolonged half-lives and reduced elimination
rates for benzodiazepines requiring oxidative metabolism prior to
glucuronidation (ie, diazepam, clonazepam, chlordiazepoxide, and alprazolam)
due to the impairment of the oxidative process. Impairment of the oxidative
process and resulting prolongation of the half-lives of these benzodiazepines
may also occur due to advanced age (22,23). As one example of cytochrome P-
450 enzyme effects, norfluoxetine (a metabolite of fluoxetine) may lead to the
inhibition of the liver microsomal system responsible for alprazolam
metabolism, resulting in clinically significant changes in the half-life and
clearance of this benzodiazepine (22). Lorazepam, oxazepam, and temazepam
avoid phase I metabolism via cytochrome P-450 enzymes and are conjugated
directly in phase II metabolism; as such they are often the preferred agents in
situations where there are concerns about liver function, age, and medication
interactions.
TABLE 56-2 Sedative–Hypnotic Withdrawal Symptoms
Another common occurrence during withdrawal is the reemergence of symptoms

of anxiety and insomnia, which has been found to occur in 60–80% of
benzodiazepine-dependent patients who were initially treated for these disorders
(24–28). Initially, these reemergence symptoms are perceived to be more severe
and intense than the original symptoms, but within several weeks return to
pretreatment levels. Although there is some debate as to the validity of the
“protracted abstinence syndrome,” these residual symptoms are thought to
persist for weeks to months and in some cases even years. Smith and Wesson
(29) suggest that receptor-mediated changes lead to worsening of withdrawal
symptoms when patients are tapered from the remaining, low-dose, medication.
Prolonged or protracted withdrawal symptoms may include anxiety, sensitivity
to light, sound, and touch (30), and tinnitus (31). In contrast to symptom
reemergence, protracted withdrawal symptoms often wax and wane and slowly
resolve with continued abstinence.
It has been estimated that up to 50% of those who use benzodiazepine on a
regular basis will experience clinically significant signs of withdrawal with
sudden discontinuation (32). The duration and intensity of use necessary to cause
withdrawal symptoms is unclear. Some sources suggest that it may take as little
as 4-6 weeks (25), while rebound insomnia has been seen after just 2 weeks of
daily drug use (33).
MANAGEMENT OF WITHDRAWAL
The decision to discontinue or taper sedative–hypnotic medications should be
discussed at length with patients, with education provided about the reasons for
discontinuation, the signs and symptoms that are likely to be experienced, and
the risks and benefits of the available withdrawal strategies. There are several
strategies that may be employed in the management of sedative–hypnotic
withdrawal. The approach with the most data to support its safety and efficacy
includes slowly tapering a medication over a prolonged period of time, in an
effort to minimize the withdrawal symptoms. One benefit of this strategy is that
it can be safely completed in an outpatient setting. Modest evidence exists to
support more acute and rapid medically supervised withdrawals, similar to the
approach taken in alcohol withdrawal treatment, though this is generally not as
well tolerated as a prolonged taper (34). The later approach also requires close
observation and monitoring and thus should only be undertaken in a closely
supervised setting. Emerging evidence supports the use of certain
anticonvulsants for the treatment of alcohol withdrawal, indicating there may be
a role for the use of similar agents in the treatment of sedative–hypnotic
withdrawal (34–36). However, there is little to no evidence that their use will
prevent more a severe withdrawal course, including seizures and delirium
tremens, especially in higher risk patients. The use of phenobarbital in the setting
of an acute medically supervised withdrawal has also been studied, though the
evidence to support this treatment is limited and somewhat dated. Flumazenil
has also been studied for use in the management of benzodiazepine withdrawal.
Benzodiazepine Taper
The approach with the most data to support its safety and efficacy is a taper that
uses decreasing doses of the currently used medication over the course of 4-12
weeks (37–39). This is most often used in settings of long-term use and physical
dependence when there is not an urgent need to abruptly discontinue the current
medication. While this method could be used in settings where there are issues
of non-medical use and use disorder, this approach is not recommended in such a
context because it would provide the patient with continued doses of the
medication for a period of weeks to months—creating risk for worsening of
substance use disorder, or diversion. In order for this strategy to be effective, the
patient must be able to follow complex dosing regimens, adhere to regular
follow-up appointments, and be free of other active substance use disorders. It is
recommended that as lower doses are achieved, the dose reduction at each stage
be more modest, especially if short half-life drugs are being prescribed. More
frequent dosing intervals can also be used in the later stages to help prevent the
emergence of any withdrawal symptoms.
There is an increased likelihood of withdrawal symptoms with medications
with a short half-life, even during prolonged tapers. Another withdrawal
management strategy involves conversion of the therapeutic agent to an
equivalent dose of a longer acting medication, and then a gradual reduction in
the dose of the latter, using the principles described above. Agents such as
clonazepam (40) and chlordiazepoxide are especially good choices given their
long half-lives and their slower onset of action and therefore relatively lower
addiction and diversion potential.
Short-acting benzodiazepines, like the triazolobenzodiazepines alprazolam
and triazolam, warrant special consideration as they can be particularly difficult
to taper. Traditionally, these medications have been thought to have a higher
binding affinity at a subpopulation of benzodiazepine GABA receptors that are
not targeted by other benzodiazepines (41). There is limited evidence to support
this, or the notion that other, longer acting, benzodiazepines may not have fully
effective cross-tolerance and may be less effective when they are used for
tapering and withdrawal management. There are case reports that suggest that
clonazepam can be used effectively for the treatment of triazolobenzodiazepine
withdrawal (40), while others have reported distinct withdrawal symptoms with
alprazolam (21,42).
A recent Cochrane review found that cognitive behavioral therapy
interventions provided some short-term benefit when combined with a
medication taper, though this benefit did not extend past 3 months, and
motivational interviewing combined with a taper did not provide any additional
benefit (43).
Anticonvulsants
Another strategy for the treatment of withdrawal is the use of anticonvulsants,
with an emphasis on the data that supports the use of carbamazepine. This
anticonvulsant has been shown to be as effective as oxazepam in the treatment of
alcohol withdrawal (44), and two open-label studies also demonstrated the
effectiveness of this agent in the management of complicated benzodiazepine
withdrawal (45,46). One multisite, placebo-controlled study suggested that
carbamazepine could also be effective for the treatment of alprazolam
withdrawal, but the findings were limited by a high dropout rate. Based on these
initial studies, the suggested dosing of carbamazepine is in the range of 200 mg
three times a day for 7-10 days. Clinical experience suggests that this strategy is
effective, but because of the potential for serious adverse events during sedative–
hypnotic withdrawal, patients should be monitored closely, and benzodiazepines
should be used as needed, especially for elevated vital signs or other
uncontrolled symptoms. Carbamazepine has the distinct advantage of having low
misuse potential and limited cognitive side effects, especially during short-term
use. These properties make carbamazepine an attractive option in patients who
are beginning a treatment program while also undergoing medically supervised
withdrawal.
Studies have also shown gabapentin and divalproex to be effective in the
treatment of alcohol withdrawal in patients who experience mild to moderate
symptoms (35), and gabapentin has some limited initial data that supports its use
in the treatment of benzodiazepine use disorders in a specific patient population
(47). While these medications have not been directly studied in the context of
sedative–hypnotic withdrawal, there is reason to suggest that these agents could
be used in this context, but further research is needed.
Another medication that warrants further investigation is pregabalin. There
is some evidence to support its efficacy in the treatment of benzodiazepine and
alcohol withdrawal, but additional research is needed to better understand its
safety and efficacy in this context (48).
Many of these studies excluded patients at risk for severe withdrawal,
including seizures and DTs, and as such these agents should be used with caution
in more complicated populations at risk.
Phenobarbital
Smith and Wesson (49,50) elucidated a protocol for utilizing phenobarbital for
medically supervised withdrawal by converting patients from other sedative–
hypnotics to equivalent phenobarbital doses. The starting daily dose of
phenobarbital should be based on the patient’s drug use during the previous
month. In cases when this is not known, a pentobarbital challenge test (51) can
be used to determine the starting dose. (The maximum starting dose is 500 mg
daily.) The daily dose should be administered in divided doses, three times a day,
and then tapered by 30 mg a day. Signs of phenobarbital intoxication are similar
to those seen with other sedative–hypnotics and include slurred speech, ataxia,
and nystagmus. If signs and symptoms of intoxication are present, then the total
daily dose should be decreased by 50% or more and the patient reassessed at
frequent intervals until the intoxication resolves. This strategy has limitations
due to the aforementioned narrow therapeutic index of phenobarbital compared
to benzodiazepines.
Flumazenil
Another treatment strategy for managing benzodiazepine withdrawal that is
being studied involves the use of flumazenil (52–57). The data on the use of
flumazenil are limited and still emerging, but published reports and studies
suggest that parenteral and subcutaneous flumazenil may be effective in the
management of benzodiazepine withdrawal. As described above, flumazenil is
used to counteract benzodiazepine toxicity and can precipitate severe
withdrawal, so the use of this agent to manage withdrawal is not intuitive and
warrants explanation. While flumazenil is generally thought of as a pure
antagonist, it acts as a partial agonist with weak affinity at the benzodiazepine
receptor site. Explanations for flumazenil’s potential efficacy in the treatment of
withdrawal symptoms include flumazenil-induced changes in receptor sensitivity
and binding affinity, though the exact mechanism of action in ameliorating
withdrawal symptoms is not clear (58,59). The evidence supporting the use of
flumazenil is preliminary at this point—there is not a consensus on the efficacy
of this treatment and therefore not generally agreed upon strategy for dosing.
Factors that may limit the use of this strategy include the method of
administration of the medication and the treatment setting, as intravenous
infusion would necessitate an appropriately monitored environment such as an
inpatient unit.
Protracted Withdrawal Symptoms

One additional consideration is the treatment of residual symptoms of
withdrawal in the days and weeks following the discontinuation of the
medication used to manage the withdrawal. The phenomenon of prolonged or
protracted withdrawal has been commented on and studied in a limited way to
date, but parallels could be drawn with the work done on understanding the
nature and effective treatment of protracted alcohol withdrawal symptoms. There
are no definitive pharmacological options for the treatment of protracted
benzodiazepine withdrawal symptoms, and this is a subject that is in need of
further investigation and understanding. Pharmacological strategies with
antidepressants, antihistamines, alpha adrenergic agents, anticonvulsants,
buspirone, melatonin, and others have been described, but there is not an
evidence base to support the use of a particular agent or strategy (60–64).
TREATMENT SETTING
While discussing with the patient the pharmacological strategy for the treatment
of withdrawal, a decision must also be made regarding the setting in which the
withdrawal will be treated. While inpatient treatment is often optimal because of
the close observation and controlled environment, this is often not feasible due
to limited accessibility to inpatient resources and cost considerations. Therefore,
inpatient treatment of withdrawal should be limited to cases in which the patient
is medically compromised, or a high risk of the patient developing severe
symptoms, such as seizures, exists. This may be the case in patients who have
been taking high doses of sedative–hypnotics for a long period of time and who
require a rapid withdrawal, or abrupt discontinuation, of the medication.
Medically supervised withdrawal on an inpatient basis may also be appropriate if
the patient has been taking multiple sedative–hypnotics or is alcohol dependent.
Patients who have a history of experiencing severe withdrawal when they have
previously stopped using sedative–hypnotics are also at high risk for having their
withdrawal complicated by serious side effects.
Medically supervised outpatient withdrawal is reasonable if the patient does
not appear to be at risk for severe withdrawal, especially if the method of slowly
reducing the sedative–hypnotic dose can be utilized. If outpatient management is
undertaken, the patient should be given clear instructions and close follow-up
appointments. If a gradual dose reduction approach is employed, it is
recommended that the patient be seen each time there is a dose reduction, and if
this is not possible, then there should be a mechanism by which the patient can
access the provider to address any questions or concerns. It is preferable for the
patient to have some level of supervision by friends or family, but this is not
always possible. Urine drug screens and clinical and laboratory assessments for
the use of alcohol should be utilized to monitor for complications that could
arise from the concomitant use of other substances.
TREATMENT OF CO-OCCURRING
DISORDERS
Medically supervised withdrawal should not be seen as definitive treatment in
the case of sedative–hypnotic use disorder. This is the first step in the
management of patients who often have other substance use disorders, anxiety
and sleep disorders, and other co-occurring medical and psychiatric disorders. In
the case of other substance use disorders, a treatment plan should include co-
occurring medically supervised withdrawal from other substances, and substance
use disorder treatment in an appropriate setting. When treating patients with
underlying anxiety and sleep disorders, other pharmacological and
psychotherapeutic treatments, particularly cognitive–behavioral therapy, should
be initiated to counter any reemerging symptoms that may be experienced
following withdrawal, which may help to reduce the risk of relapse (64–67).
Other co-occurring psychiatric disorders should also be addressed during, or
soon after, withdrawal. Failure to stabilize anxiety, sleep, or other co-occurring
conditions will likely lead to higher rates of relapse due to patient discomfort,
limited compliance, and inability to effectively engage in the early stages of
rehabilitative treatment.

DIRECTIONS
Sedative–hypnotic medications have been used for many years for a variety of
disorders and symptoms. Today, benzodiazepines are by far the most commonly
used sedative–hypnotics, and their use is widespread. The appropriate use of
benzodiazepines requires a clear understanding of the medications, an accurate
diagnosis and treatment plan, and close monitoring. Most individuals who use
sedative–hypnotic medications take their medications as prescribed and do not
manifest non-medical use or develop a substance use disorder. Physical
dependence may be unavoidable in cases of prolonged use; therefore,
benzodiazepines should be prescribed for the shortest period of time that is
clinically reasonable. Potential withdrawal signs and symptoms should be
initially discussed with patients before treatment with this class of medications is
initiated. Prescribers must be aware of the risks inherent in prescribing
benzodiazepines and other sedative–hypnotics, but they should be careful not to
withhold treatment when appropriate. If providers and patients are well informed
and openly discuss the risks and benefits of these medications, and they are
prescribed at reasonable doses, sedative–hypnotics can be used safely and
effectively for the treatment of a number of otherwise disabling conditions.
Sedative–hypnotics continue to be widely prescribed, and while these
medications are relatively safe when taken alone, their use in conjunction with
opioids is receiving increased attention. The risk of death in the context of
concurrent sedative–hypnotic and opioid use has led to renewed debate and
discussion about the overall efficacy and safety of the sedative–hypnotic
medications, and in many cases, it precipitates a more urgent need to address
issues related to overdose and withdrawal. Pharmacological strategies to manage
intoxication and withdrawal are limited in their scope and the evidence base to
support newer strategies, and manage protracted withdrawal symptoms, needs to
be expanded so that patients and prescribers have more options at their disposal.
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CHAPTER 57
Pharmacological and Psychosocial
Treatment for Opioid Use Disorder
David Kan, Joan Zweben, Susan M. Stine, Thomas R.
Kosten, Elinore F. McCance-Katz, and John J. McCarthy
CHAPTER OUTLINE
Introduction
History and context of opioid agonist treatment
Modern historical understanding of OUD
Overview of pharmacologic interventions
Abstinence syndromes and medically supervised withdrawal
Long-term treatments for OUD
Special issues in ongoing medication treatment
Patients with co-occurring psychiatric disorders
Psychosocial interventions
Oversight and regulatory challenges
INTRODUCTION
In 2016, 1.9 million American adults had an opioid use disorder (OUD) related
to prescription pain relievers, and 586,000 related to heroin. According to the
Centers for Disease Control and Prevention (CDC), sales for prescription opioids
nearly quadrupled between 1999 and 2014, while deaths rose to over 165,000.
Approximately three out of four heroin initiates used prescription opioids before
switching to heroin (1,2). As of September 2017, synthetic opioids such as
fentanyl were responsible for more overdose deaths than prescription pain
relievers or heroin (3).
Of the estimated two million persons with OUD in the United States in 2016,
~360,000 are enrolled in federally licensed programs offering opioid agonist
treatment (OAT) in 49 states except for Wyoming (4,5). The 1460 specially
licensed opioid treatment programs (OTPs) in the United States offer counseling,
testing, and pharmacotherapy using methadone (and buprenorphine in certain
facilities), with daily dispensing or strictly regulated take-home medication for
selected patients (5). There are currently 24,767 prescribers authorized to
prescribe buprenorphine for OUD under the DATA 2000 act (6). Of those
prescribers, <50% prescribe buprenorphine for OUD (7), but 12.5 million
buprenorphine prescriptions were written in 2016 (8). This chapter focuses on
OAT in the context of the licensed methadone OTP and office-based
buprenorphine for OUD treatment, which has been supported by World Health
Organization (WHO), Surgeon General, Office of National Drug Control Policy
(ONDCP), National Governors Association, National Institute on Drug Abuse
(NIDA), and the U.S. Department of Health and Human Services (HHS) (9–11).
HISTORY AND CONTEXT OF OPIOID

AGONIST TREATMENT
Dole and Nyswander demonstrated the feasibility and efficacy of opioid agonist
pharmacotherapy (OAT) using methadone in the 1960s (12), but some negative
attitudes toward OAT have stemmed from the misguided perception of OAT as
“just substituting one addicting drug for another.” However, OAT is not simple
substitution but provides stabilization or correction of neuroadaptations to
chronic opioid exposure (13). OAT provides cross-tolerance and blockade of the
opioid system (14,15), and is associated with decreased mortality, reduced illicit
drug use, reduced seroconversion to human immunodeficiency virus (HIV),
reduced criminal activity, and increased engagement in socially productive
activities (16–21). Nevertheless, US regulatory requirements continue to
stigmatize OAT and create barriers to providing treatment (22). Physicians
sometimes refuse to treat a patient who discloses that he or she is receiving OAT.
Occasionally, patients are told that they must withdraw from OAT to receive
treatment for other medical conditions. A physician may withhold medication
needed for symptomatic relief, thus causing unnecessary discomfort and pain.
Many patients with OUD enter OAT with great ambivalence and want to
discontinue OAT, which is consistent with the short-term treatment that many
practitioners, policy makers, and regulators seem to favor. However, studies
demonstrate that only 10% to 20% of patients who quickly discontinue OAT are
able to remain abstinent (17,23–26), which is similar to most chronic medical
conditions that also require ongoing medication.
MODERN HISTORICAL
UNDERSTANDINGS OF OUD
Medication has demonstrated efficacy in the treatment for OUD, but biologic,
psychosocial, and cultural variables also impact OUD and may need attention.
Prior to the discovery of the opioid receptor system, Dole and Nyswander (27)
conceptualized OUD as a “metabolic disease,” a view that won Dr. Dole the
Albert Lasker Clinical Medicine Research Award in 1988 (13). He wrote in the
Journal of the American Medical Association (14):
It is postulated that the high rate of relapse of addicts after

detoxification from heroin use is due to persistent derangement of the
endogenous ligand narcotic receptor system and that methadone in an
adequate daily dose compensates for this defect…. The treatment,
therefore, is corrective but not curative for severely addicted persons.
A major challenge for future research is to identify the specific defect
in receptor function and to repair it. Meanwhile, methadone
maintenance provides a safe and effective way to normalize the
function of otherwise intractable opiate addicts.
In Dole’s view, the persistent receptor dysfunction is the result of chronic opioid
use, leading to down-regulation of the modulating system and possibly also to
suppression of the endogenous ligands. Goldstein (14) supported the concept of
a genetic and metabolic disease and suggested that genetic influence carries an
exceptional vulnerability to the disease in the presence of certain environmental
influences. Kreek (81) and others suggested that multiple genes may account for
different degrees of vulnerability to developing addiction (28–32).
Positron emission tomography of cerebral metabolism in patients with OUD
compared with patients withdrawn from methadone and in sustained remission
suggests that methadone treatment at least partly normalizes cerebral glucose
metabolism (33). Magnetic resonance spectroscopy comparing patients receiving
methadone with different elapsed treatment times showed a nearly normal
phosphorus metabolism profile in those patients who had been in long-term
OAT, suggesting resumption of pre-disease reactivity at the neurochemical level
over time (34).
OVERVIEW OF PHARMACOLOGIC
INTERVENTIONS
The principal opioid medications used to treat OUD are the opioid μ-receptor
antagonists naloxone and naltrexone; the full agonists methadone, levo-alpha-
acetylmethadol (LAAM), heroin, and hydromorphone; the partial agonist
buprenorphine; and the nonopioid α2-adrenergic agonists clonidine and
lofexidine.
Opioid Antagonists
Naltrexone is a long-acting, orally and parenterally effective, predominantly μ-
opioid antagonist that provides complete blockade of μ-opioid receptors when
the oral formulation is taken at least three times a week for a total weekly dose
of about 350 mg (35). Because the reinforcing properties of opioids are blocked,
naltrexone is theoretically an ideal agent in the treatment of patients with OUD
who can successfully complete withdrawal and maintain abstinence from
opioids.
Opioid Full and Partial Agonists

Methadone
Methadone is an orally active, long-acting synthetic opioid. Increasing doses of
methadone reduce abstinence signs and symptoms and drug craving. Effective
methadone doses ranging from 80 to 120 mg/d also produce a resistance to the
effects of intravenously administered heroin, hydromorphone, and methadone.
The term agonist blockade was coined to describe this phenomenon.
Levo-Alpha-Acetylmethadol (LAAM)
LAAM is the α-acetyl congener of methadone. Its principal difference from
methadone is its longer half-life and its conversion to the active metabolites
norLAAM and dinorLAAM. It is approved by the U.S. Food and Drug
Administration (FDA) for treatment in OTPs but is no longer marketed owing to
low demand in the wake of reports of an association with cardiac arrhythmias
(torsade de pointes [TdP]).
Buprenorphine
Buprenorphine is a high-affinity μ-opioid partial agonist and κ-opioid antagonist
that the FDA approved as a pharmacotherapy for OUD in October 2002 (36,37).
Despite its higher unit-dose cost compared to methadone, buprenorphine has
expanded access to OUD treatment due its availability through office-based
practice. This could reduce the disparity between the number of individuals with
OUD and the number of available treatment slots and facilitate general medical
care of such individuals (38–40).
Heroin and Hydromorphone
Heroin and hydromorphone are short-acting μ-opioid agonists. Heroin is
classified as a Schedule I drug by the Drug Enforcement Administration (DEA).
Routes of administration include insufflation, smoking, and injection. Although
illegal in the United States, heroin treatment has been used in select patients and
jurisdictions internationally to treat OUD. Studies of heroin treatment
demonstrated reduced illicit heroin use, health status improvements, increasing
employment, and decreased crime (41–43). Importantly, heroin treatment is
typically reserved for individuals who have failed repeated attempts at
methadone treatment (43). Hydromorphone is a Schedule II medication. A recent
randomized, controlled trial indicated that it is also effective for individuals who
have failed methadone treatment (44).
Nonopioids: α-Adrenergic Agents

Clonidine
Clonidine is a centrally acting α2-adrenergic receptor agonist. It decreases
adrenergic neurotransmission from the locus coeruleus through feedback
inhibition. Clonidine is FDA approved for the treatment of hypertension but is
used off label for the medical management of opioid withdrawal. Many of the
autonomic symptoms of opioid withdrawal result from the loss of opioid
suppression of the locus coeruleus system during the abstinence syndrome (13).
Side effects of sedation and hypotension limit the use of clonidine in opioid
withdrawal. One recent study indicated that combining clonidine with
buprenorphine for treatment of OUD reduced opioid craving and use compared
to buprenorphine combined with placebo (45).
Lofexidine
Lofexidine, like clonidine, is also a centrally acting α2-adrenergic agonist,
recently approved by the FDA in the United States. It is used for the medical
management of opioid withdrawal. It is associated with less hypotension that
limits the use of clonidine for withdrawal treatment.
ABSTINENCE SYNDROMES AND

MEDICALLY SUPERVISED
WITHDRAWAL
The opioid abstinence syndrome is characterized by two phases (46): a relatively
brief initial phase in which patients with physiologic dependence on opioids
experience acute withdrawal followed by a protracted abstinence (PA) syndrome.
Current pharmacologic strategies are designed to address these two distinct
phases, acute withdrawal and protracted withdrawal. The acute withdrawal
syndrome lasts from 5 to 14 days and consists of a wide range of symptoms.
Symptoms include gastrointestinal distress (such as diarrhea and vomiting),
disturbances in thermal regulation, insomnia, muscle pain, joint pain, marked
anxiety, tremor, and dysphoria. Although these symptoms generally include no
life-threatening complications, the acute withdrawal syndrome causes marked
discomfort, often prompting continuation of opioid use, even in the absence of
any opioid-associated euphoria. Longer-term, PA symptoms are discussed in this
chapter under long-term treatments. Medically supervised withdrawal without
OAT results in high relapse rates and overdose risk (47,48). An essential point
always to bear in mind is that withdrawal from opioids does not represent
definitive treatment for OUD, and the vast majority of patients return to use after
withdrawal without continued medication treatment (49–55).
Medically supervised withdrawal is discussed briefly next and in greater
detail elsewhere in this text.
Opioid Agonists and Partial Agonists

Opioid-based medically supervised withdrawal is based on the principle of
cross-tolerance, in which one opioid is replaced with another that is then tapered.
Methadone is often used because it has a long half-life and can be administered
once daily. Withdrawal is usually managed with initial dosages of methadone in
the range of 15-30 mg/d (56). Although this dosage is generally adequate to
control symptoms in many individuals who use opioids, additional methadone
can be given as required based on clinical findings. However, a simple
conversion of short-acting prescription medications into an equivalent dosage of
methadone can lead to overdose as methadone accumulates over the first several
days of dosing. Thus, any methadone dose over about 40 mg daily should
involve careful and slow dosage increases over at least several days. Various
guidelines that are available for conversion from short-acting opioids to
methadone typically suggest giving half of the calculated equivalent methadone
dose to any patient with a calculated dose of more than 50 mg daily of
methadone (57,58). The conversion ratio of methadone is highly variable
depending on factors such as patient tolerance, morphine equivalent dose, and
length of dosing (short-term vs. chronic dosing). Because the analgesic duration
of action (6-8 hours) is shorter than the half-life (24-36 hours), toxicity due to
drug accumulation can occur with just a few doses.
In acute medical settings, this starting dosage should be maintained through
the second or third day after the peak dose is attained, and then the methadone
can be slowly tapered by ~10% to 15% per day. Although in the United States a
licensed physician can perform supervised methadone withdrawal in an inpatient
medical setting when the primary reason for hospital admission is not OUD,
longer-term, outpatient withdrawal using methadone must be performed in a
federally licensed OTP.
Buprenorphine can also be used for opioid withdrawal. Buprenorphine’s
slow dissociation from μ-opioid receptors results in a long duration of action and
also has milder withdrawal signs and symptoms on discontinuation than full
agonists (49,50,59–62), making it useful for medically supervised withdrawal
from opioids. The extant literature contains various findings on the length of a
buprenorphine taper with limited evidence favoring a more rapid taper (36) and
some supporting a more prolonged taper. On the basis of current knowledge, the
recommended clinical approach is to stabilize the patient within a day on a dose
of buprenorphine that suppresses most withdrawal signs and symptoms, typically
8 to 16 mg/24 hours. The dosage can then be tapered over a time frame as brief
as 3 days or extending for weeks or even months depending upon patient and
clinician goals and preferences.
The optimum dose of buprenorphine for acute inpatient opioid withdrawal
has not been determined. A meta-analysis (63) compared buprenorphine treated
opioid withdrawal to other established methods. This meta-analysis selected
randomized controlled trials involving the use of buprenorphine compared to
interventions involving reducing doses of methadone, α2-adrenergic agonists,
other symptomatic medications, or placebo. Studies examining different rates of
buprenorphine reduction were also considered in this meta-analysis. Overall, 22
(1736 participants) were included. The major comparisons were with methadone
(5 studies), clonidine, or lofexidine (12 studies). While no significant difference
was observed in the incidence of adverse effects, dropout due to adverse effects
may be more likely with clonidine. Overall conclusions were that buprenorphine
more effectively controlled withdrawal signs and symptoms than did clonidine
or lofexidine and may also offer some advantages over methadone in terms of
quicker resolution of withdrawal symptoms.
Nonopioid Medication Treatments

Clonidine
Early clinical studies demonstrated that clonidine diminished withdrawal
symptoms in patients who were withdrawn from methadone (64,65). Clonidine
seems to be most effective in suppressing autonomic signs and symptoms of
opioid withdrawal but is less effective for subjective withdrawal symptoms (66).
Initial daily doses of up to 1.2 mg per 24 hours in divided doses are commonly
suggested. For example, a regimen of 0.1-0.2 mg every 4 hours has been used in
two clinical trials for heroin withdrawal, with careful monitoring of blood
pressure. Because it may be less effective in managing subjective withdrawal
symptoms, adjuvant therapy (nonsteroidal anti-inflammatory drugs [NSAIDs]
for myalgia, benzodiazepines for insomnia, medications for diarrhea, and
antiemetics) may be needed (53,67). Multiple studies have described clonidine’s
use in medically assisted withdrawal (53,68).
Lofexidine and Other α2-Adrenergic Agonists

The use of clonidine in the management of opioid withdrawal has been
hampered by limited long-term efficacy and side effects including sedation and
hypotension. This in turn has led to the investigation of the effectiveness of other
α2-adrenergic agonists—lofexidine, guanfacine, and guanabenz acetate—in the
management of opioid withdrawal, to find a drug that has clonidine’s capacity to
manage the signs and symptoms of opioid withdrawal but with fewer side
effects.
Lofexidine, a centrally acting α2-adrenergic agonist, has, after clonidine,
been the most used and investigated α2-adrenergic treatment for opioid
withdrawal.
Lofexidine treatment is typically initiated at 0.18 mg twice daily, increasing
daily by 0.18-0.36 mg.(69) The package insert of the recently approved product
suggests 0.54 mg qid (twelve 0.18 mg tablets per day) with a maximum daily
dose of 2.88 mg (16 tablets per day). Doses required to decrease withdrawal
symptoms, however, vary for each patient depending on the amount, frequency,
and duration of opioid used. In numerous randomized trials, lofexidine was
found superior to placebo and generally equivalent to clonidine in reducing signs
and symptoms of opioid withdrawal. It appeared to cause less hypotension than
clonidine. Lofexidine was somewhat less useful than methadone at managing
signs and symptoms of withdrawal (68,70–76). The most common adverse event
with lofexidine was somnolence, and hypotension was also reported. Overall,
lofexidine has a decreased incidence and severity of side effects compared with
clonidine.
Medication Combinations, Rapid and

Ultrarapid Opioid Withdrawal
Because most opioid and nonopioid approaches to medically supervised
withdrawal require a prolonged timeframe of a week or more, “rapid” and
“ultrarapid” opioid withdrawal protocols have been attempted (77,78). These
“rapid” protocols use an opioid antagonist (eg, naloxone or naltrexone) to cause
an accelerated withdrawal response, with the goal of completing the withdrawal
portion in shorter periods from 8 days to as little as 2 or 3 days. In addition to an
opioid antagonist, rapid approaches use pharmacotherapies (eg, clonidine and
sedation procedures) in an attempt to minimize the acute withdrawal symptoms
experienced when opioid antagonists are administered. These methods for
transition to naltrexone in < 7 to 10 days from physiologic opioid dependence
have shown efficacy in a recent multisite study (78a), but are not in widespread
use. Ultrarapid methods are similar in pharmacologic approach to the rapid
method, use general anesthesia and complete the procedure in several hours, and
are associated with life-threatening adverse events. Ultrarapid withdrawal
management was not found to be superior in long-term efficacy to the use of
buprenorphine or clonidine in a 2006 review and therefore was not deemed to
justify the risks of general anesthesia (79).
LONG-TERM TREATMENTS FOR OUD

Clinical Issues in Ongoing Pharmacotherapy
Goals of Pharmacotherapy of OUD
Kreek (80,81) outlined the goals of treatment and the properties of desirable
opioid agonist medications as follows:
1. Prevention or reduction of withdrawal symptoms

2. Prevention or reduction of opioid craving
3. Prevention of relapse to use of addictive opioids
4. Restoration to or toward normalcy of any physiologic function disrupted by
chronic opioid use
Notably, like other medical conditions, the goals are focused on controlling signs
and symptoms of the condition rather than discontinuation of medication
treatment. This helps to provide a useful framework when patients, clinicians,
and policymakers inquire as to the appropriate length of pharmacotherapy.
Profile of Potential Medications to Treat OUD

Characteristics of potential medications can be defined as follows:
1. Such medications are effective.

2. They have a long biologic half-life (>24 hours).
3. They have minimal side effects during chronic administration.
4. They are safe (ie, they lack true toxic or serious adverse effects).
5. They are efficacious for a substantial proportion of persons with the
disorder. Methadone and buprenorphine are agonists, and naltrexone is an
antagonist generally exhibiting these characteristics.
Opioid Physical Dependence and Protracted Abstinence

Himmelsbach (80), reporting on 21 prisoners dependent on morphine, observed
that “physical recovery requires not < 6 months of total abstinence.” Martin and
Jasinski (46) reported in a subsequent study that the period of protracted
abstinence (PA) persisted for 6 months or more after withdrawal and that it was
associated with “altered physiologic function.” They found decreased blood
pressure, decreased heart rate and body temperature, miosis, and a decreased
sensitivity of the respiratory center to carbon dioxide, beginning about 6 weeks
after withdrawal and persisting for 26-30 or more weeks. They also found
increased sedimentation rates (which persisted for months) and
electroencephalograph (EEG) changes. Martin and Jasinski (46) postulated a
relationship between the PA syndrome and relapse. In another study, Shi et al.
(82) also studied PA symptoms in individuals who formerly used heroin,
comparing those who were not receiving medication and those receiving
methadone after similar lengths of heroin abstinence. Seventy individuals who
had formerly used heroin were included in one of four groups: in days 15-45 of
short-term methadone treatment (MT), in months 5-6 of MT (long-term MT), no
opioids for 15-45 days after methadone-assisted heroin withdrawal (short-term
post methadone), and no opioids for 5-6 months after methadone-assisted heroin
withdrawal (long-term post methadone). Analysis of PA symptoms during the
study allowed the investigators to conclude that long-term methadone treatment
reduces PA symptoms of heroin abstinence and cue-induced craving.
The concept of PA has been controversial (83) but remains a useful model
for scientific hypothesis testing and development of new therapeutic approaches
(84). As Dole pointed out, since methadone continues physical dependence, PA
may remain a problem later if medically supervised withdrawal from methadone
is undertaken. In addition to biologic considerations, psychosocial concomitants
of OUD also necessitate longer, more specialized adjunct treatments for these
and additional problems.
Treatment Using Methadone

Continued Illicit Opioid Use Versus Methadone
Treatment
The person with OUD who is actively using heroin or other short-acting opioids
typically experiences rapid and wide swings from a brief pleasure usually
characterized by relief of withdrawal symptoms, sedation, fading into a period of
normalcy and alertness, which can be described as the “comfort zone.” This
period is uniformly followed by the beginnings of subjective withdrawal, which
soon develops into the full objective withdrawal syndrome typical of OUD. This
cycle is particularly evident in the patient who engages in injection or inhalation
of potent short-acting opioids such as heroin. A full cycle from “sick”
(withdrawal) to “high” (intoxication) to “normal” (alert, comfortable) to “sick”
(withdrawal) can occur repeatedly throughout the day (Fig. 57-1). The sensation
of the “rush” is associated with a very rapid increase in blood levels. The
pleasure is experienced during the time that drug levels remain above the
therapeutic window (Fig. 57-2). OATs, such as methadone or buprenorphine
regularly administered at steady state, are present at levels sufficient to maintain
alertness without craving or drug preoccupation (comfort zone or therapeutic
window) throughout the dosing interval—usually 24 hours.
Figure 57-1 Heroin-simulated 24-hour dose–response.
Figure 57-2 Methadone 24 hours at steady state.
With each administration of methadone, there is a gradual rise in blood level,

reaching a peak at 3-4 hours. Typically, the peak level is less than two times the
trough level. There is a gradual decline over the rest of the 24-hour period, back
to the trough level. When the patient is on the correct dose at steady state and
with development of sufficient tolerance, at no time does the rate or extent of
change in blood levels cause a sensation of being intoxicated or result in
Methadone Induction
Although most patients eventually will need 80-120 mg/d of methadone to
achieve stability (19), and although adequate doses are needed to provide
stability and retention in treatment (85),the starting dose must be much lower,
and the eventual steady state is reached slowly over many days to weeks. The
first several doses require careful evaluation and adjustment. This phase is called
induction. Even though methadone treatment has been shown to reduce
mortality, including overdose mortality (86,87), several studies have reported
deaths during the first 10-14 days of treatment, particularly when induction
doses are high and particularly if the patient is also ingesting sedatives (88–92).
About 42% of drug-related deaths during treatment occurred during the first
week of OAT (93). In one study, patients were reported to be 6.7 times more
likely to die during induction as compared to untreated individuals using heroin
(90). The mean induction dose was more than 50 mg among those who had died.
All cause mortality dropped sharply over the first 4 weeks of methadone
treatment, but the induction phase onto methadone treatment and the time
immediately after leaving treatment are periods of particularly increased
mortality risk (21). Variability in methadone metabolism, discussed later in the
section on drug interactions, may also be a factor.
Initial Dose
In most cases, patients being evaluated for admission to OAT have developed
significant tolerance to opioids and therefore demonstrate objective signs of
withdrawal as evidence of current opioid physical dependence. The response to
the initial dose of agonist medication provides valuable information about
tolerance levels and the target “therapeutic window.” Significant relief during
peak methadone effect (2-4 hours) indicates that the dose is in the range of the
established level of tolerance and may not require further escalation. The
absence of relief suggests that the dose is well short of the therapeutic window.
Additional methadone can be provided when significant objective withdrawal
persists during peak methadone levels. Patients who come in 24 hours after their
very first dose can be expected to be uncomfortable as tissue store accumulation
is still incomplete. If they were comfortable during the first 4-12 hours after their
dose, they probably need more time at the same dose and not a higher daily dose.
Under federal regulations, the initial dose of methadone is no more than 30 mg
and may be lower in patients in whom low tolerance might be expected (eg,
recent relapse after a significant period of abstinence, or addiction to lower-
potency opioids such as hydrocodone or codeine, or in opium smokers).
Identification of low tolerance is the principal task of the initial medical
assessment after confirming the diagnosis of OUD. An additional dose of 10mg
of methadone may be administered on day one of dosing if documentation is
present that withdrawal is inadequately suppressed with the initial 30-mg dose. A
total dose of no more than 40 mg may be given on the first treatment day unless
the program physician documents in the patient’s record that 40 mg did not
suppress opioid abstinence symptoms.
Stabilization and Steady State

After the initial dose, the induction phase allows for subsequent careful
adjustments of the dose to achieve elimination of drug craving and prevention of
withdrawal while avoiding the risk of intoxication or overdose associated with
accumulation of methadone (94,95). The induction phase can be considered to
last until the patient has attained a methadone dose that meets the four goals
outlined above. The safe and effective introduction of methadone requires an
understanding of steady-state pharmacologic principles. In general, steady-state
levels are reached after a drug is administered for four to five half-lives
(methadone has an average half-life of 24-36 hours). The clinical significance is
that, with daily dosing, a significant portion of the previous dose remains in
tissue stores, resulting in increased peak-and-trough methadone levels after the
second and subsequent doses. Thus, the blood levels of methadone increase
daily, even without an increase in dose. The rate of increase levels off as steady
state is achieved at four to five half-lives, that is, 3-7 days (Fig. 57-3). Further
dose changes every 3-7 days may be needed to achieve the maintenance dose.
Dose adjustments can be done in 5- to 10-mg increments for highly tolerant
patients. Liquid medication allows dose adjustments by smaller increments for
less tolerant patients.
Figure 57-3 Steady-state simulation—maintenance
pharmacology attained after four to five half-times, 1
dose/half-life.
Duration and Dose

Dose level and duration of treatment are individualized clinical decisions. There
is no scientific or clinical basis for an arbitrary dose ceiling on methadone,
although QT prolongation has been seen in the electrocardiograms of patients
receiving high doses of methadone (95). Methadone doses of 80-100 mg have
greater benefits than doses below 50 in heroin-dependent patients (96–98). For
most patients receiving methadone, a long-term approach is most appropriate.
Based on an extensive review of the research literature on the prognosis of
patients who have been withdrawn from methadone, as well as the safety of
continued treatment, the American Society of Addiction Medicine supports the
principle that methadone treatment is most effective as a long-term modality
(99).
The known risks of discontinuing methadone treatment, with predictable
return to use to injected heroin or fentanyl use, become increasingly critical
when viewed in the context of overdose and the HIV and Hepatitis C Virus
(HCV) prevalence among people who inject drugs. These risks, when combined
with the proven safety and efficacy of long-term methadone treatment, suggest
that long-term—even indefinite—methadone treatment is appropriate and even
essential for a significant proportion of eligible patients. Methadone treatment is
therefore a treatment of a chronic medical disorder, with the goal of achieving
control of the opioid addiction and avoiding the ravages of the untreated disease
(100). Treatment should be continued as long as the patient continues to benefit,
wishes to continue, remains at risk of relapse to opioid or other substance use,
and suffers no significant adverse effects and as long as continued treatment is
indicated in the professional judgment of the physician (101). Patients receiving
methadone do at times seek to discontinue maintenance for nonmedical but very
real and practical reasons (eg, transportation or scheduling difficulties) and to
escape continued disruption of their lives associated with the burdensome
restrictions, regulations, and structure of the treatment delivery system.
Regulations permit clinic attendance just once a month with take-home doses for
the other days for long-term, stable patients. For patients who attempt
withdrawal, it is important for practitioners to provide encouragement along with
the best medical and supportive treatment available, without fostering unrealistic
expectations or unnecessary guilt, and to provide a means for rapid readmission
to methadone treatment in the event of relapse or impending relapse to the use of
illicit opiates (99).
Techniques to Ensure Adequacy of Dose

In most cases, clinical observation and patient reporting are adequate to make
appropriate dose determinations. In rare cases in which patients fail to stabilize
on methadone and continue to complain of withdrawal symptoms and craving
even at daily dose of 120 mg or greater, evaluation of methadone blood levels
may be indicated.
Procedure for Obtaining Blood Levels

Peak blood levels should be drawn at 3 (2-4) hours after a dose and trough levels
at 24 hours, once said dose has been stable for at least 5 days, to allow tissue
store equilibration. Patients already on a divided dose, such as every 12 hours,
should have 2- to 3-hour and 12-hour specimens. A trough level alone is of little
clinical value unless it is extremely low or very high. Blood levels are
interpreted in the context of a clinical presentation for which the laboratory
values can supplement clinical judgment. The peak level at 2-4 hours should be
no more than twice the trough level. A peak-to-trough ratio of 2 or less is ideal
(peak/trough = ratio). Ratios >2 suggest rapid metabolism. The rate of change is
of greater clinical significance than the actual levels. For example, a patient with
a 24-hour level of 350 ng/mL after a peak of 1225 ng/mL (1225/350 = 3.5,
indicating rapid metabolism) may be experiencing early opioid withdrawal,
whereas a patient with a trough of 150 ng/mL and a peak of 250 ng/mL (250/150
= 1.7, indicating a normal metabolism) may be quite comfortable. No particular
blood level should be considered “therapeutic” outside of the clinical context.
Observed Doses and Take-Home Medication in OAT

Patient stability reduces need for daily visits. Patients who do well and who
improve per specified criteria set out in US federal regulations can receive take-
home medications. The criteria include adherence to treatment, stability of home
environment, involvement in productive activity, abstinence from illicit
substance use, and resolution of any legal problems. As of March 2017, the
guidelines governing methadone treatment allow patients to take home up to six
doses a week after 9 months, 2 weeks of medication after the first year, and 30-
day doses after the second year of treatment (42 CFR 8.12).
Monthly observed dosing at the OTP, with take home doses for the month, is
as close as most patients receiving methadone come to receiving their
medication in a fashion like that in other well-controlled medical conditions.
Methadone medical maintenance (MMM) and office-based opioid treatment
(OBOT) with methadone remain a rarity in the United States.
Methadone Medical Maintenance

MMM, designed for “stable, recovered” patients on methadone, is an effort to
release the patient from attendance in an OTP by allowing a physician who is
affiliated with the clinic, but in office practice, to prescribe or administer
methadone. In April 2000, the CSAT circulated draft guidelines describing
medical maintenance. These guidelines were developed after more than 10 years
of pilot projects and showed that this approach to care works and that it
improves the quality of life for patients (102). A 2001 study randomly assigning
patients to either office- or OTP-based methadone showed no difference in
clinical outcomes and improved patient and physician satisfaction (103).
For those who are attempting to receive ongoing treatment in a different
setting rather than from the effects of daily medication, medical maintenance
could be an acceptable solution. Current regulations require a federal waiver for
medical maintenance; however, as of 2018, MMM is still rarely used.
Methadone–Medication Interactions
Clinical experience suggests that concomitant medications can either induce or
inhibit cytochrome (CY) CYP450 activity on methadone metabolism (104).
Drugs that stimulate or induce CYP450 activity can precipitate opioid
withdrawal by accelerating metabolism, thus shortening duration and
diminishing intensity of the effect of methadone. For example, addition of ethyl
alcohol, rifampicin, phenytoin, carbamazepine, phenobarbital, nevirapine, or
efavirenz may result in the onset of withdrawal symptoms and require dose
adjustments of methadone. Considerable flexibility in dosing may be required to
stabilize some patients whose metabolism has been altered by medication
interactions or have increased rates of metabolism due to other causes. Other
medications such as cimetidine, ciprofloxacin, fluconazole, erythromycin, and
fluvoxamine may inhibit this enzyme activity, slowing the metabolism and
extending the duration of the medication effect. Metabolism of methadone is
largely a function of enzyme activity in the liver, and intestinal enzymatic
activity has also been observed to be clinically relevant. Multiple CYP450
isoenzymes may affect methadone metabolism in vivo (105). Liver 3A4 activity
in vitro is shown to influence methadone metabolism (106). Methadone exists as
a racemic mixture of R and S isomers. Genetic variability in CYP2D6 activity
may affect clinical status by affecting metabolism of the R-methadone isomer
(107–109) and may also affect toxicity (110). Enzymatic activity of intestinal
CYP2B6 is stereoselective and may be important in clinical effects and drug
interactions (111). A 17-fold variability between patients in their methadone
metabolism is shown, mostly due to activity of various CYP450 enzymes (112).
Due to variability in methadone metabolism, it is important for clinicians to
focus on functional outcomes rather than absolute dose amounts when
determining the appropriateness of treatment.
Methadone and QT Interval

Several case series have been published showing that methadone treatment is
associated with prolongation of the QT interval on the electrocardiogram and
possible consequent cardiac arrhythmia (Torsade des Pointes or TdP) (113,114).
In 2006, the FDA published a boxed warning that included QT interval
prolongation and the risk of arrhythmia.
In vitro study of human ether-à-go-go–related gene potassium channels
(hERG K+) confirms that methadone at therapeutic doses can affect cardiac
conduction (115). Genomics of CYP2B6 were shown to be associated with QT
interval, and in vitro studies suggest that most of this prolongation is due to the
nontherapeutic S-methadone enantiomer (116). Interviews of patients receiving
methadone treatment found an association between longer QT and retrospective
self-report of syncopal episodes (117). Several studies look at QT interval in the
methadone clinic setting (118–120). However, there are no clear data to guide
any intervention. Some clinics are offering cardiograms and are screening
patients for cardiac risk. Risk–benefit discussion with patients includes a review
of other medications that might contribute additional cardiac risk, eliciting a
history of structural heart disease, unexplained syncopal episodes, or familial
prolonged QT syndrome. All of these conditions may heighten the risk for TdP
and may warrant ECG screening. In general, it is considered that almost certain
relapse to uncontrolled opioid use is more risky than the rare occurrence of an
arrhythmia. However, coordination of care with outside physicians to monitor
the use of other medications or transfer to buprenorphine treatment might in
some cases be indicated (121). Hospitalized patients receiving methadone may
have particularly high risk of TdP (121). The Center for Substance Abuse
Treatment (CSAT) convened a consensus panel on this topic, and the final
iteration of the consensus panel’s recommendations include risk assessment and
ECG screening, patient and staff education about cardiac risk, and informed
consent (122,123). However, this advice was not based upon solid evidence of
preventing deaths and did not include a cost-benefit assessment. Thus, the
support of the panel for this viewpoint was not unanimous. Feasibility of
offering QT screening on-site in the OTP has been shown in several studies
(122,124), but substantial barriers remain including cost, staff time, and access to
cardiologists to read the tracings. It has not become standard of care to do
routine ECG screening in licensed OTPs.
Benzodiazepines and OAT Including Methadone

The potentially lethal combination of benzodiazepines with OAT is important to
address in patients who have concomitant benzodiazepine use or benzodiazepine
use disorder. For patients with therapeutic sources of benzodiazepines, careful
coordination with prescribing physicians is indicated. Alternate treatments for
insomnia or anxiety may be possible. Abrupt cessation of high doses of
benzodiazepines may require medically supervised withdrawal due to the risk of
withdrawal seizures. Reported rates of benzodiazepine misuse among
methadone-treated patients are between 24.9% and 50.6% (125).
Benzodiazepine testing should be a routine in OTPs (126). A recent retrospective
chart review of 278 OAT patients showed patients prescribed benzodiazepines
had longer treatment retention and lower mortality than patients who never
received benzodiazepine prescriptions. However mortality significantly
increased once patients receiving benzodiazepines left treatment (127).
Medical Monitoring of Methadone

The initial pharmacologic rationale for long-term methadone maintenance was
its ability to relieve the PA syndrome and to block heroin euphoria (48,128). No
serious side effects are associated with continued methadone use (129) with the
exception of hypogonadism in men, sleep apnea (130), and risk of QT
prolongation with exceedingly rare but potential subsequent progression to TdP
(122). Minor side effects, such as constipation, excess sweating, peripheral
edema, drowsiness, and decreased sexual interest and performance, have been
noted. In addition, neuroendocrine studies have shown normalization of stress
hormone responses and reproductive functioning after several months of
stabilization on methadone (131).
Buprenorphine Treatment
In October 2002, the FDA approved two sublingual formulations of
buprenorphine for treatment of DSM-IV opioid dependence. In the initial FDA-
approved formulation, a combination of buprenorphine and naloxone in a 4:1
ratio was designed to discourage injected diversion and misuse. There are now
four FDA-approved buprenorphine/naloxone products for the treatment of OUD
that are administered sublingually or through buccal administration. The
originally approved formulation had a buprenorphine:naloxone ratio of 4:1.
Current formulations range from buprenorphine:naloxone from 7:1 to 3.88 to 1.
Newer formulations were approved based upon demonstrating the production of
equivalent serum levels of buprenorphine compared with the 4:1 product.
Technologies deployed to allow for lower doses of buprenorphine include saliva
pH modification to enhance buprenorphine absorption as well as the
development of bioerodible mucoadhesives (BEMA). Naloxone is an opioid
antagonist that is not significantly bioavailable when taken sublingually or when
swallowed. When injected into individuals actively using opioids who are
blinded, the buprenorphine/naloxone combination was not judged to be desirable
or to be different from the antagonist in the first hour after injection (132,133).
This buprenorphine/naloxone combination is the preferred formulation for
outpatient use as an effort to minimize diversion. The other sublingual
formulation contains only buprenorphine and is used in controlled settings, such
as inpatient medically supervised withdrawal, or in pregnancy.
Pharmacology of Sublingual/Buccal Buprenorphine

Buprenorphine has slow onset and long duration of action, conferring similar
benefits as discussed earlier for methadone. As a partial mu agonist,
buprenorphine has a maximal dose–effect ceiling that is well below significant
respiratory depression for most patients. This safety profile led to its DEA
Schedule III, allowing office-based use under the restrictions of the Drug
Addiction Treatment Act of 2000 (134).
Pharmacology of Implantable Buprenorphine

An implantable buprenorphine matrix was FDA approved in 2016. Implantable
buprenorphine binds buprenorphine with ethylene vinyl acetate polymer. Each
rod contains 74.2 mg of buprenorphine. Four rods are implanted into subdermal
tissue in the upper arm. This formulation is indicated for patients who are stable
for a minimum of 3 months on buprenorphine/naloxone 8 mg/2 mg or an
equivalent dose. The implants last 24 weeks and must be removed after 24
weeks.
In one study, 114 subjects received buprenorphine implants, 54 subjects
received placebo implants, and 119 subjects received open-label buprenorphine–
naloxone combination product at doses of 12 to 16 mg sublingual daily (135).
Buprenorphine implant subjects had a mean proportion of opioid-negative urine
drugs screens of 31.2% compared with 13.4% of patients with the placebo
implant. Sixty four percent of patients with the buprenorphine implant
completed the study compared with 26% of placebo implant patients. The
buprenorphine implant also results in a lower rate of cocaine use. The rate of
opioid-negative urine drug screens was not significantly different between
buprenorphine–naloxone sublingual products and buprenorphine implant. Side
effect profiles were similar between buprenorphine implant and buprenorphine–
naloxone sublingual medication except for implant site reactions in 27% of
buprenorphine implants. Commonly reported implant side reactions include
hematomas and pain.
A second phase III trial was conducted with 177 participants who were
already stable on buprenorphine 8 mg daily or less. Subjects receiving the
buprenorphine implant had a statistically significant improvement in achieving
continuous opioid use remission (85.7% vs. 71.9%) during the 6-month study
period (136).
Both of these studies demonstrated the efficacy and safety of buprenorphine
implants, but neither study has had long-term outcome follow-ups.
Buprenorphine implant recipients currently are counted under a provider’s cap in
the DATA 2000 waiver.
Pharmacology of Injectable Buprenorphine

Sustained-release injectable (SR) buprenorphine was approved and released in
the United States in March of 2018. SR buprenorphine is a buprenorphine-only
product administered subcutanously in abdominal tissue. SR buprenorphine is
available in 300 mg and 100 mg doses to be given once monthly. One 12 week
study of SR buprenorphine showed blockade of drug liking effects of
intramuscular hydromorphone after two injections of SR buprenorphine (137). A
24 week study with SR buprenorphine administered at 300mg on months one
and two followed by administration of four 100 mg doses monthly demonstrated
superiority to placebo producing more illicit opioid-free weeks (138). In both
studies, patients receiving SR buprenorphine were stabilized on eight to 24 mg
of sublingual buprenorphine prior to receiving SR buprenorphine. Serum levels
of SR buprenorphine were comparable to sublingual buprenorphine doses
usually used to treat OUD. SR buprenorphine has detectable serum levels for up
to one year after six injections.
Induction and Precipitated Withdrawal

Buprenorphine has strong receptor affinity. Relative to a displaced full agonist,
its activity can be felt as the rapid onset of (relative) opioid withdrawal by the
patient unless the first dose is clinically well timed. The first dose should be
given when the patient is already in mild to moderate opioid withdrawal. When
opioid withdrawal is present, the onset of activity will be felt as agonist, with
relief of withdrawal. In contrast to methadone, induction doses are not set by
regulation, though clinical guidelines and physician training courses recommend
2-4 mg of sublingual buprenorphine/naloxone as a first dose, with first-day
maximum of 8 mg (139). One study found that higher induction doses were
associated with better engagement in ongoing care (140). There has been one
case series showing the successful transition from high-dose full agonists using
concomitant transdermal buprenorphine to allow for the initiation of sublingual
buprenorphine without precipitated withdrawal (141). More research in this area
is recommended to produce protocols that limit patient discomfort between
transitions from full agonists to partial agonist therapy.
Induction Setting
The majority of published studies have conducted buprenorphine inductions with
supervised dosing. The advantages of supervised dosing include attenuation of
withdrawal symptoms under medical supervision. However, observed inductions
require significant staff time and monitoring. Observed induction logistics are
seen as a barrier to buprenorphine prescribing (142). There is a growing practice
and body of evidence that supports the feasibility and safety of unobserved or
“home” inductions particularly from office-based practices (143).
Buprenorphine Dose Adjustment

The dose of buprenorphine can be titrated over the first 3 days to control
withdrawal. Average daily doses are 16-20 mg. One labeled imaging study
showed mu opioid receptors to be ~90% occupied depending upon the brain
region at doses of 16 mg/d of sublingual solution (144). Because of the partial
agonist ceiling effect, no additional benefit is expected in doses above 32 mg/d.
Sublingual buprenorphine/naloxone is usually prescribed as a single daily dose.
Buprenorphine–Medication Interactions
Compared to methadone, buprenorphine may confer advantages when certain
HIV medications are used (145) and in cases of QT prolongation with
methadone (120,146). The presence of an active metabolite—norbuprenorphine
—and strong affinity for the mu opioid receptor make this medication less
dependent than methadone on blood level and tissue stores.
Federal Regulations and Sublingual Buprenorphine

When dispensed in the OTP, sublingual buprenorphine/naloxone is subject to the
same regulations as methadone, except for the observed dosing requirements, as
explained below. When prescribed in the office-based setting, there are certain
restrictions set forth in the Drug Addiction Treatment Act of 2000. This law
provides for a waiver to the 1914 Harrison Act that forbids prescription of a
“narcotic” to a person with an addiction. The qualifying prescriber notifies the
Secretary of Health and Human Services of his or her intent to prescribe, after
which the DEA assigns to the prescriber a second DEA registration number that
is specifically for use under DATA 2000. There are restrictions on census and
type of medication and rules on storage and record keeping. Physicians, nurse
practitioners, and physician assistants can receive the DATA 2000 waiver. The
DATA 2000 restrictions do not apply when buprenorphine or
buprenorphine/naloxone are dispensed at clinics under their OTP license. In
those cases, the same federal regulatory restrictions apply to both buprenorphine
and methadone except that the time-in-treatment regulations that apply to take-
home doses of methadone no longer apply for buprenorphine so that decisions
about the number of buprenorphine take-home doses given are determined
purely based on patient stability and not on how long the patient has been in
treatment. Alternate-day or thrice-weekly dosing is an option for the
buprenorphine-maintained patient who is not stable enough to have take-home
doses (147,148).
Diversion and Nonmedical Use of Buprenorphine

An early and limited investigation of the effects of DATA 2000 was carried out
in 2005. No serious adverse events were found by the introduction of sublingual
buprenorphine/naloxone in the office-based setting. That study showed that most
of the patients treated with buprenorphine listed prescription pain relievers as
their primary opioid of misuse (149). In view of the increase in nonmedical use
of prescription opioids, it is hoped that buprenorphine/naloxone may provide a
timely treatment for those who become addicted and who might not otherwise
seek out a methadone clinic.
Wherever buprenorphine treatment has been introduced, there has been
diversion and nonmedical use of the medication, including injected use
(150,151). As the clinical use of buprenorphine has increased since 2002, so
have reports of diversion. One study in the United States showed that diverted
buprenorphine/naloxone is being used mostly for relief of withdrawal and rarely
as a primary drug of misuse (152). A more recent study found that diversion
increased as treatment with buprenorphine became more available, though not as
steeply as full agonists (153). In areas of higher prescribing of buprenorphine,
most treatment seekers have already tried the medication, having used it illicitly
for relief of withdrawal or during times when the preferred opioid of misuse is
not available (154). Buprenorphine diversion suggests a lack of OUD treatment
availability (155). An Australian study that interviewed patients who were found
to be diverting doses given under observation at pharmacies found that
discarding it, saving it for another time, or giving the dose to someone else were
cited as reasons for not taking an observed dose (156,157). Buprenorphine has
two- to threefold lower rates of drug diversion reports compared with methadone
and other full agonist opioids (155,158,159). Guidelines for agonist treatment
recommend monitoring for diversion with urine testing or pill counts and adding
observed dosing or shortening time span between prescriptions when diversion is
suspected. Long-acting buprenorphine formulations such as the implant or
sustained release injection are options as well.
SPECIAL ISSUES IN ONGOING

MEDICATION TREATMENT
Comparative Efficacy of Buprenorphine
Versus Methadone: Choice Between
Methadone and Buprenorphine
The clinical issue of choosing between pharmacotherapy options or matching
patients to buprenorphine versus methadone maintenance continues to be an
open question that is actively investigated. Early studies offered few head-to-
head comparisons, and those available had limited dose comparisons. Treatment
retention is higher with LAAM, high-dose methadone (80 mg/d), and
buprenorphine than low-dose methadone (30 mg/d) (160,161). A meta-analysis
published in 2014 (20) found that buprenorphine is an effective intervention for
use in the treatment of OUD, and it is as effective as methadone delivered at
adequate dosages. A study by Ridge et al. (162) demonstrated that
buprenorphine was more likely to be prescribed for short-term opioid withdrawal
and methadone for maintenance treatment. A large longitudinal study of opioid-
dependent outpatients selected from 10 Italian Public Services for Addiction
centers in Naples (Italy) (163) examined the use of treatment with the
buprenorphine/naloxone combination and also compared these patients to
patients receiving methadone. In patients treated with buprenorphine/naloxone, a
significant improvement was reported in social life status, educational level, and
urine toxicology outcomes compared with methadone treatment.
Though both medications have been shown to be comparable in various
outcomes (160,161) systematic reviews suggest that methadone and
buprenorphine are roughly equivalent in reducing illicit opioid use with
methadone demonstrating slightly better rates of treatment retention (164,165).
In the United States, site of care and level of care, local availability, or cost may
determine which medication is applicable for a given patient. A blinded study
showed that a “stepped” approach of starting patients on buprenorphine and
transferring those who did not stabilize onto methadone had identical outcomes
to directly admitting patients to methadone treatment (166).
Buprenorphine may confer less cardiac risk (117,146), although no
prospective studies have been carried out. A randomized prospective liver safety
study showed no liver damage produced by either medication (167).
Opioid Agonist Treatment during Pregnancy

Opioid misuse during pregnancy is a growing concern in the United States and
internationally and is often associated with adverse consequences for both the
mother and her infant, especially prematurity and low birth weight (168–176).
From 1998 through 2011, there was a 127% increase in pregnant women with
OUD presenting for delivery (177). The current literature suggests that children
of women with OUD might be at risk for poor outcomes not only because of
opioid drug exposure but also because of concomitant alcohol and tobacco
exposure and numerous factors related to the caregiving environment (172,178).
Treatment options studied include methadone or buprenorphine (179,180),
antagonist maintenance (181) (ie, naltrexone), and medication-assisted
withdrawal (182). Methadone has been the recommended standard of care over
no treatment or medication-assisted withdrawal. This is based on longer
durations of maternal drug abstinence, better obstetrical care compliance,
avoidance of associated risk behaviors, reductions in fetal illicit drug exposure,
and enhanced neonatal outcomes (179). Methadone is the oldest, most widely
used medication prescribed during pregnancy (180), and in comparison to
infants from mothers using heroin, infants from methadone-treated mothers have
increased fetal growth, reduced fetal mortality, and decreased risk of HIV
infection (171,183). Moreover, for pregnant women under conditions where
nonmedication and methadone treatment were both available, methadone is
associated with longer treatment retention (184,185) and less relapse (183).
Studies examining the consequences of prenatal methadone exposure on later
development have produced inconsistent results (186–192) that could be due to
confounding factors and are complicated by study attrition (192). Overall,
methadone treatment in pregnancy does not appear to be associated with
developmental or cognitive impairments (186–192).
Nevertheless, methadone use at effective clinical doses during pregnancy
may be avoided by some practitioners due to concerns over the associated
neonatal abstinence syndrome (NAS). Although newborns of women receiving
methadone may experience NAS, these are readily treated without consequences
(192). Furthermore, dose is not a reliable proxy for fetal exposure since the fetus
is not exposed to the maternal dose but to the maternal serum level, which is
largely determined by individual patient pharmacogenomics and
pharmacokinetics (193). (See discussion below in NAS subheading.) Hence,
pregnant women should receive appropriate methadone doses to treat their
addiction (194). Large, definitive randomized controlled trials of buprenorphine
in pregnant women have not been conducted. There have been 31 published
reports of buprenorphine exposure during pregnancy that were reviewed and
summarized by Jones et al. (194) Overall, the pregnancies were uneventful,
without physical teratogenic effects and with low rates of prematurity,
suggesting that buprenorphine is relatively safe and effective in this population.
Conclusions from data on the prenatal exposure to buprenorphine are limited by
methodologic challenges (eg, varied dose ranges, lengths of exposure, care
settings). Many reports omitted information regarding concomitant substance
use and prescribed medications that could impact the expression of NAS.
However, there is a lack of detailed studies of fetal physiology during
buprenorphine induction, which could cause acute maternal/fetal withdrawal and
pose potential hypoxic problems for the fetus (195). The Maternal Opioid
Treatment: Human Experimental Research (MOTHER) study (165) was a large
multisite clinical trial enrolling a diverse sample of pregnant opioid-dependent
women into both methadone and buprenorphine treatment. The methadone group
had better retention (the most important variable in drug treatment outcomes):
treatment was discontinued by 18% of methadone patients and 33% of
buprenorphine patients. However, infants born to mothers in the buprenorphine
group required less morphine, had a shorter hospital stay, and had a shorter
duration of treatment for the NAS. There were no differences between groups in
other primary or secondary outcomes or in the rates of maternal or neonatal
adverse events. The authors conclude that buprenorphine is an alternative to
methadone for the treatment of OUD during pregnancy. While buprenorphine
appears to be associated with reduced severity of NAS, methadone dosing was
done as a single daily dose in the MOTHER study, rather than the divided dosing
dictated by pharmacokinetic science and clinical studies (196). More research is
needed into optimal dosing of both medications. Dosing that does not address
the variability in drug elimination between mothers or that limits maternal dose
to an arbitrary limit (the MOTHER study set a dose limit of 140 mg/d that is
below the needs of many rapid metabolizing mothers) ignores the risk of
protracted and/or episodic stressfulmaternal–fetal withdrawal and potential
adverse effects on neonatal health (193).
Clinicians should also take into account the possibility of reduced adherence
and the ceiling effect of buprenorphine compared with methadone. It is unknown
how many buprenorphine practices provide the intensity of medical monitoring
needed by pregnant women. Methadone regulations require intensive clinic
attendance, monitored dosing, a counselor, and an actively involved physician
who meets regularly with the patient. The higher rate of treatment
discontinuation in the buprenorphine group raises issues of optimal induction
onto buprenorphine and retention as an issue for future exploration.
Comparison studies have been done in specific clinical areas. Prospective,
randomized, and blinded studies during pregnancy and the perinatal period show
that both methadone and buprenorphine are safe, with methadone associated
with more severe NAS (165,197–199).
Neonatal Abstinence Syndrome

NAS is an important outcome for OAT in pregnancy. Nevertheless, across
studies, there is often insufficient detail regarding medication used to treat
ensuing NAS as well as the criteria for initiation, maintenance, and weaning of
NAS medication. Sublingual buprenorphine shows promise in one placebo-
controlled trial in significantly reducing length of hospitalization for NAS when
compared to oral morphine (200). Although the scoring systems used to assess
NAS treatment efficacy vary across reports (eg, Finnegan et al. (201) or
modifications of this scale and Lipsitz (202)), the literature suggests that
buprenorphine is associated with NAS, half the cases of which require
pharmacotherapy. The pregnancy, birth, and NAS outcomes are confounded by
other drug use in 86% of the reports. Although considerable individual
variability exists, the NAS timing observed to date has an apparent onset within
the first 12-48 hours, peaks within ~66-96 hours, and lasts ~120-168 hours. The
exception to this has been the few infants who were reported to exhibit
withdrawal signs for 6-10 weeks after delivery (203,204). These cases may
represent protracted abstinence, as seen with adults, or neonatal ill health related
to adverse pregnancy events beyond simple opioid exposure, such as illicit drug
use and long-term effects of chronic intrauterine withdrawal stress. To date, only
one report has found a correlation between buprenorphine dose and the severity
of the NAS (205). Other reports (197,206,207) have reported no correlation.
Research has demonstrated that NAS is not managed consistently after
delivery (208). There is likely major overuse of Neonatal Intensive Care Units
for uncomplicated withdrawal leading to unnecessary maternal/fetal separations
at a time critical for bonding. A rooming-in model of care where the mother and
fetus are not separated and where the mother is an active part of NAS
management has been shown to reduce NAS symptoms and length of
hospitalization (209). The OTP physician should explain the advantage of
rooming-in to the mother and encourage her to discuss this option with her
doctors.
Intrauterine Abstinence Syndrome

Intrauterine abstinence syndrome (IAS) has received little attention until recently
(195). Maternal and fetal withdrawal usually coincide, and the fetus is at risk of
seizures, hyperactivity, and catecholamine excess. This increases fetal oxygen
consumption and risk for asphyxia. Because of these risks, medically supervised
withdrawal from opioids during pregnancy is not recommended (210).
Increasing evidence shows unfavorable intrauterine conditions affect developing
systems and produce epigenetic changes associated with adult disease and long-
term behavioral abnormalities (211,212). While fetal demise is not a common
outcome with maternal opioid withdrawal during pregnancy (213), relapse
exposes the fetus to erratic drug levels and to episodic withdrawal. The ASAM
and the American College of Gynecology jointly recommend against the practice
of medically supervised withdrawal because of the high risk of relapse (214).
OAT with partial or full agonists should be offered to all female patients with
OUD when pregnancy is discovered for the health of the mother and developing
fetus no matter the determination to continue or terminate the pregnancy.
Methadone dosing in pregnancy is complicated by the clinical need to
respond to the altered metabolism caused by pregnancy-related induction of the
key metabolic enzymes, which convert the active medication to an inactive
metabolite (215). The variable timing and rate of enzyme induction during
gestation dictates that dose increases are likely to be required at any stage of
pregnancy to minimize maternal/fetal withdrawal symptoms and divided doses
are routinely needed to manage the reduced half-life of the medication (196).
Further, divided dosing eliminates or minimizes fetal physiologic abnormalities
seen with single-dose methadone treatment (216,217). Pharmacokinetic science
should be the basis for dosing to minimize withdrawal stress by maintaining a
stable level of mu receptor occupancy in both maternal and fetal brain (193).
Methadone trough serum levels provide an objective window on both
maternal metabolism and fetal exposure. This information can document the
need for dose increases and reduce anxiety about adverse effects of increased
doses on the fetus. It is not uncommon to see the methadone dose go up and the
serum level go down or remain constant (196). Further, serum levels postpartum
are necessary for clinical safety to monitor the reversal of enzyme induction and
a rise in serum levels, which can pose problems of oversedation, higher than
normal amounts of methadone entering breast milk, and maternal dependence on
unnecessarily high serum levels (193). Most women will need dose decreases in
the early postpartum period.
Buprenorphine is converted to three active metabolites: norbuprenorphine
and the glucuronide conjugates of the parent and norbuprenorphine (193,218).
Therefore, serum levels are likely to remain more constant than methadone and
require less frequent dose adjustments. However, accelerated metabolic effects
can also affect buprenorphine metabolite levels, and dose increases and divided
dosing are likely needed for optimal maternal/fetal mu receptor occupancy, as
with methadone (219).
The treating clinician should partner with an obstetrician and neonatologist
in the management of a pregnancy in the context of OUD. Consultants may lack
understanding of the nature of addiction and the special issues related to
maternal/fetal OUD, leading to negative physician–patient interactions and
maternal stress and shame (193). Pregnant women are especially reassured to
know that their physicians communicate and agree on a treatment plan.
Interactions of Opioid Agonist Treatment and Human

Immunodeficiency Virus and Acquired
Immunodeficiency Syndrome Pharmacotherapy
The introduction of new antiretroviral agents and antiretroviral therapy (ART)
created a new therapeutic era for HIV-infected patients but also has introduced
new complexities related to potential toxicities and interactions. Preclinical
studies of ART and opioids indicate that drug interactions may occur as
methadone and buprenorphine are both primarily metabolized by hepatic
cytochrome CYP4503A4 (106,220). A number of antiretroviral medications
have been shown in preclinical studies to inhibit or induce the activity of this
same enzyme.
Methadone has been associated with several clinically important adverse
drug interactions with ART. Significant drug–drug interactions between
methadone and antiretroviral medications include potential for opiate withdrawal
symptoms with efavirenz, nevirapine, lopinavir/ritonavir, and rilpivirine while
methadone levels may be increased as a result of inhibition of methadone
metabolism with delavirdine, although this medication is rarely used for the
treatment of HIV infection at this time. Medications known to inhibit CYP3A4
have been used as a means of enhancing the plasma concentrations of other HIV
medications. These include ritonavir and cobicistat, but neither has a clinically
significant effect on methadone metabolism. Antiviral medications for the
treatment of hepatitis C including, boceprevir, sofosbuvir, and telaprevir have no
significant drug interactions with methadone (221).
Antiretroviral medications that induce methadone metabolism present a risk
for methadone toxicity if discontinued without concurrent tapering of methadone
dose that had been increased to assure therapeutic effect of methadone while
treatment with the inducing medication occurred (155). It has been
recommended that after the medication that is inducing CYP4503A enzymes is
stopped, the methadone dose should be tapered over 1-2 weeks to reestablish the
previous therapeutic dose of methadone (ie, that dose on which the patient was
stable before starting the antiretroviral medication that induced methadone
metabolism) (5).
Buprenorphine has been studied in combination with antiretroviral
medications more recently. To date, reductions in buprenorphine concentrations
resulting from drug interactions have not been associated with opioid
withdrawal. Further, a recent review (145) regarding specific interactions
between buprenorphine and ART found that drug interactions between
buprenorphine/naloxone and HIV medications are less likely than with
methadone.
Methadone-to-Buprenorphine Transfer
Some patients will be transferred from methadone to buprenorphine. This
clinical decision may be driven by several possible factors. First, there is the
unique pharmacology of buprenorphine, leading to its more favorable safety
profile and longer duration of action (thus permitting thrice-weekly dosing)
relative to methadone (61,222–224). Second buprenorphine may engender less
fear of stigma than methadone (225). Third, owing to its availability in office-
based primary care—outside standard OTPs (52,73,226)—buprenorphine is
more accessible over a wide geographic area. It also may be more appropriate as
an early intervention strategy for those with short OUD histories (eg,
adolescents) or with less physical dependence. However, if a patient is stable on
methadone, the advisability of transfer to buprenorphine requires careful scrutiny
of the factors motivating the request. Furthermore, transferring patients from a
long-acting agonist such as methadone to buprenorphine without producing
significant withdrawal discomfort, attrition, or relapse to drug use has been
shown to be more challenging than transfer from a short-acting opioid.
Research on transfer from methadone to buprenorphine is limited. These
studies support an important role for methadone dose and interval between
methadone and buprenorphine administration in determining precipitated
withdrawal symptoms. Four studies examined the effect of time interval between
the last methadone dose and the initial buprenorphine dose (227–230). Most
subjects received methadone at 30 mg/d. Buprenorphine has a lower risk of
precipitating withdrawal the greater the time between the last methadone dose
and the first buprenorphine dose (227,228,230–233). Buprenorphine transitions
from methadone doses of 30 mg/d are generally well tolerated (234).
Buprenorphine induction from methadone doses of 60 mg/d risks increasing
opioid withdrawal symptom (230). Two additional studies (231,233) showed
mild withdrawal with buprenorphine initiation from methadone, but withdrawal
severity was not correlated with methadone dose. Five studies have directly
examined a full medication transfer (231,233,235,236). Precipitated withdrawal
was not consistently seen with the transition from methadone to buprenorphine.
Some patients were not adequately treated with buprenorphine. If a patient
experiences precipitated withdrawal with the initial buprenorphine dose,
additional doses of buprenorphine are not likely to worsen withdrawal and may
produce greater comfort (237). Lofexidine may assist in the transition from
methadone doses of 30-70 mg to buprenorphine (238).
Owing to variable designs and individual differences among volunteers, a
single recommended protocol is not currently available. In the absence of large
clinical trials, the Provider Clinical Support System (PCSS) guidance (PCSS
2013) recommends tapering to 20 or 30 mg of methadone, waiting a minimum of
48 to 72 hours after last methadone dose, obtaining a COWS of 15 to quantify
withdrawal, and starting buprenorphine at 2 mg, continuing to dose until the
patient is comfortable at up to 32 mg on day 1. If withdrawal is precipitated,
management with ancillary medications is advised. Discomfort may persist for
up to 96 hours, but usually after 3-5 days, the patient will be stable and
comfortable.
In addition to clarifying the best strategy for minimizing symptoms during
the transfer, clinical trials are needed to answer questions concerning short- and
long-term clinical outcomes after methadone-to-buprenorphine transfer. A
related relevant clinical need is identification of profiles and genetics of patients
responding differentially to methadone versus buprenorphine (pharmacotherapy
treatment matching).
Buprenorphine in Agonist-to-Antagonist Treatment

A number of strategies have been tried to transition patients from buprenorphine
to treatment with the antagonist naltrexone. No specific protocol has emerged as
the optimal way to affect the transfer. This procedure can be accomplished
within the span of a few days, but precipitated withdrawal can occur. Often, α2
adrenergic and other ancillary medications are needed to manage precipitated
withdrawal. There should be good justification, even if just patient preference,
for using naltrexone in this situation when patients could be stabilized on
buprenorphine or methadone much more easily.
Naltrexone Treatment
The theoretical value of the opioid antagonist, naltrexone, is tempered by clinical
reality, as reflected in retention rates of only 20% to 30% over 6 months.
Multiple factors account for such poor retention (129). Opioid antagonists,
unlike methadone and buprenorphine, do not provide cross-tolerance. Therefore,
if antagonists are stopped, there is no immediate reminder in the form of
withdrawal. In addition, craving for opioids may continue during naltrexone
treatment. A meta-analysis did not provide strong support for oral naltrexone
treatment of OUD (239). Nevertheless, for certain highly motivated subsamples
of patients with OUD (such as healthcare professionals, business executives, or
probation referrals) for whom there is an external incentive to comply with oral
naltrexone therapy and to remain opioid abstinent, oral naltrexone has been very
effective (240–243). Improved adherence has also been reported in programs
that include psychosocial therapy (244,245), including contingency management
(246,247).
Clinically, oral naltrexone is initiated after withdrawal from opioids. There
should be at least a 5- to 7-day opioid-free period for the short-acting opioids
and a 7- to 10-day period for the long-acting agents. This does not apply to
withdrawal treatments using the naltrexone–clonidine combination. The first
dosage of naltrexone may be preceded by a naloxone challenge test to assure the
absence of precipitated withdrawal prior to administering naltrexone. The initial
dose of naltrexone used generally is 25 mg on the first day, followed by 50 mg
daily or an equivalent of 350 mg weekly, divided into three doses (100, 100, and
150 mg). The principal reason for the reduced dose on day 1 is the potential for
gastrointestinal side effects, such as nausea and vomiting. This occurs in about
10% of patients taking naltrexone. In most cases, gastrointestinal upset is
relatively mild and transient, but in some cases, it may be so severe as to cause
discontinuation of the naltrexone. Oral naltrexone also has infrequent potential
to cause transaminitis; however, 50 mg daily has been given safely to individuals
with OUD (248). Transaminitis, in the rare instances it occurs, appears to be
limited in extent in that it resolves when naltrexone is discontinued and does not
progress to liver failure. The enzyme dihydrodiol dehydrogenase appears to
catalyze the metabolism of naltrexone to the active metabolite, 6β-naltrexol.
When administered orally, naltrexone has an average plasma half-life of 4 hours,
whereas 6β-naltrexol has an average half-life of 13 hours after oral
administration of the parent drug. In summary, though oral naltrexone has not
lived up to expectations, for selected, motivated patients with OUD, it may
represent a very effective form of maintenance pharmacotherapy.
Extended-release formulations of naltrexone (by implant and by depot
injection) have been investigated. An extended-release formulation of naltrexone
(XR-NTX) injected once monthly (every 4 weeks), found safe and well tolerated
by participants in studies of treatment for alcohol use disorder (249–251), was
approved for OUD by the FDA in 2010. The medication has peak drug
concentrations occurring at 2 hours and again at 2-3 days, remaining at
therapeutic levels through 30 days. The recommended dose of 380 mg of
extended-release naltrexone resulted in minimal and mild adverse events. The
most common adverse events associated with XR-NTX in clinical trials were
nausea, vomiting, headache, dizziness, and injection site reactions. It can also
reduce opioid tolerance, which can increase the potential for overdose if opioids
are used following cessation of long-term naltrexone treatment. In preliminary
studies of sustained-release naltrexone in opioid-dependent subjects, Comer et
al. (252–254) found that 384-mg XR-NTX was able to block the reinforcing,
subjective, and physiologic effects of up to 25-mg heroin and provided
therapeutic plasma levels for ~30 days (252–254). At this dose, naltrexone also
resulted in better than 80% retention in treatment at 6 weeks versus 40% for
placebo (254). Adverse events were minimal and limited to local injection site
responses (255). A trial of XR-NTX in patients with DSM-IV opioid dependence
was reported by Krupitsky (256,257). This randomized, placebo-controlled,
double-blind trial of XR-NTX was conducted in Russia, where agonist therapy is
not available (256,257). Participants received monthly intramuscular injections
of XR-NTX 380 mg (n = 126) or placebo (n = 124) for 4 months with 12
biweekly counseling. The number of weeks of confirmed abstinence (based on
rate of opioid-negative urine drug tests and self-report during weeks 5-24) was
the primary outcome. In the XR-NTX group, 90% were abstinent versus 35% for
placebo (p = 0.0002). The XR-NTX participants also had more opioid-free days,
greater retention, and reduced craving compared to no change in the placebo
group. No XR-NTX participants died, overdosed, or ended participation due to
severe adverse events associated with the study protocol. A more recent open-
label randomized trial in the United States among criminal justice–involved
individuals with OUD showed that XR-NTX was superior to treatment as usual
in preventing relapse to opioid use (257a). Ongoing research will need to address
the effectiveness of XR-NTX compared to methadone and buprenorphine and
which patients may differentially respond to this medication.
XR-NTX was compared to daily sublingual buprenorphine in two studies
(258,259). A 12-week open-label randomized clinical trial of 159 subjects
showed XR-NTX was non-inferior to daily sublingual BUP-NLX in measures of
treatment retention, total number of opioid negative urine drug screens, and use
of heroin and other illicit opioids (259). A 24-week open-label randomized
controlled comparative effectiveness study of 570 subjects showed that XR-NTX
was not successfully initiated in 28% of subjects compared with non-successful
initiation in 6% of BUP-NLX subjects. Once both medications were started,
opioid negative urine samples and opioid abstinent days favored BUP-NLX in
an intent to treat analysis but were similar in the per-protocol population. Self-
reported opioid cravings was less with XR-NTX than with BUP-NLX initially
but these converged by week 24. Five fatal overdoses occurred with two in the
XR-NTX group and three in the BUP-NLX group. These studies demonstrate
that XR-NTX has a role in the treatment of OUD but the high rate of initial
dropout with XR-NTX is of concern.
Other implant formulations of depot naltrexone are being studied; several
international implant studies are reviewed by Krupitsky and Blokhina (256). The
most studied is a single-dose Australian naltrexone implant. A double-blind,
placebo-controlled, randomized clinical trial showed the effectiveness of this
formulation in comparison with oral naltrexone (75). In comparison with the oral
formulation, naltrexone implants (not XR-NTX) showed significantly higher
abstinence rates and better treatment outcomes at 12 months (260–263). A large
clinical trial is currently underway to compare the efficacy of XR-NTX versus
buprenorphine for OUD (264).
One author (DK) is aware of several opioid overdose deaths after the
cessation of XR-NTX. According to unpublished data from a registry trial of
XR-NTX for OUD (265), 30% of patients dropped out before receiving their
first XR-NTX injection. Seventy six percent of 403 patients treated with XR-
NTX dropped out in the first 6 months. Over 90% of patients were treatment
failures during the duration of the study itself. Three patients died from overdose
within 21, 55, and 115 days of their last dose of XR-NTX. Only 8.5% of patients
discontinued XR-NTX because treatment goals were met. Naturalistic studies
raise serious questions about the safety and long-term efficacy of XR-NTX for
OUD.
Pain Management in Patients Receiving Opioid Agonist

Treatment
Patients on OAT require special consideration because of their baseline
maintenance opioid. They will be tolerant to additional opioids, and if nonopioid
approaches are not effective, they may need higher and more frequent doses of
opioids to manage their pain.
Methadone and Acute Pain Management

In cases of acute pain associated with surgery, trauma, or dental work, the
physicians or dentists involved often—incorrectly—assume that usual daily dose
of methadone will relieve any ensuing pain from the injury or procedure. Several
points should be kept in mind. First, single daily doses of methadone may be
effective in controlling addiction, but multiple daily doses may be required for
analgesia. Second, long-term use of methadone and possibly buprenorphine as
well is associated with hyperalgesia (266,267). Tolerance and hyperalgesia
combined means that patients in OAT who require opioids for acute pain
management may need very high doses of opioids. However, high-potency
NSAIDs and nonopioid analgesics can also be considered as primary or
adjunctive medications in the management for acute pain. Mixed agonist–
antagonists (pentazocine, butorphanol, nalbuphine) and partial agonists
(buprenorphine) must not be used in patients receiving methadone as they will
precipitate an opioid withdrawal syndrome. Meperidine should be avoided
because of the risk of seizures at the higher doses required to produce analgesia
in patients receiving methadone.
In summary, for patients receiving methadone who require opioids for acute
pain management, (a) continue methadone without interruption and use
nonopioid pain treatments whenever possible; (b) provide adequate
individualized doses of opioid agonists, which must be titrated to the desired
analgesic or functional effect; and (c) doses should be given more frequently and
on a fixed schedule rather than “as needed for pain.” Although not thoroughly
documented, it is probably best to choose agonists different from those
previously misused.
Buprenorphine and Acute Pain Management

Buprenorphine has a ceiling on respiratory depression. The ceiling on analgesia
is controversial. Management of acute pain (eg, postsurgical pain) on the patient
taking buprenorphine is poorly understood. Clinical guidelines recommend
increased doses of buprenorphine or tapering or stopping buprenorphine to allow
full opioid agonists access to opioid receptors to manage postsurgical acute pain
syndromes. However, these guidelines lack any scientific evidence and are
primarily based upon the known pharmacology of buprenorphine and clinical
experience. A small case series reported on five patients receiving buprenorphine
through seven major surgeries. Postoperative pain was adequately controlled
using full agonist opioids by patient report and physician assessment while
maintaining buprenorphine (268). More research is required in this important
issue as fear of unmanaged pain is often a barrier to patients accepting partial
agonist therapy for OUD.
Chronic Pain in Patients Receiving OAT

More than 30% of patients receiving OAT report chronic, severe pain (269).
Compared to those who primarily misuse heroin, patients admitted to the OTP
for prescription opioid addiction may have higher prevalence of pain (159,270).
The historical separation of pain treatment from addiction treatment in American
medicine gets in the way of properly caring for patients with chronic pain who
are receiving OAT. The OTP and office-based clinician can sometimes bridge
this gap by coordinating care with the patient’s primary care or pain specialist.
For example, in a patient with chronic noncancer pain who is able to comply
with the regulatory criteria for take-home medication, the OTP physician can
order a divided dose of methadone, and the outside physician can prescribe
short-acting rescue medication. This might improve baseline pain control
without the need for multiple sources of long-acting medication. Nonopioid
pharmacologic strategies and nonpharmacologic interventions for chronic pain
should typically be attempted before or in addition to relying solely on opioid
medications to manage chronic pain.
Improving Treatment Access Through Emergency

Departments
A randomized clinical trial tested the efficacy of various treatments for
emergency department (ED) care for the treatment of OUD. Three hundred and
twenty-nine opioid-dependent patients were enrolled. One hundred and four
patients were randomized to a referral only, 111 patients were assigned to a brief
intervention group, and 114 were assigned to receive buprenorphine and
connection with a buprenorphine prescriber. Doses of buprenorphine were 8 mg
on day 1 and 16 mg on days 2 and 3. Thirty four percent of all subjects were
seeking treatment for OUD, and 8.8% presented with an overdose. The primary
outcome at 30 days showed that 78% of patients who received buprenorphine
were receiving formal addiction treatment, while only 37% in the referral group
and 45% of patients in the brief intervention group were receiving such
treatment (271). The DEA allows for daily dispensing (not prescription) of any
opioid medication for up to 72 hours to treat OUD while arranging for more
definitive treatment.
Overdose Education and Naloxone Distribution

Overdose education and naloxone distribution (OEND) is a service that has
demonstrated efficacy and is addressed in detail in the chapter on harm
reduction. OEND traditionally has been relegated to needle exchange programs.
OEND in programs that serve high-risk individuals have served to reduce
overdose death rates in heroin-using populations. In a study of 2500 injection
drug using participants from 2010 to 2013, 702 overdose reversals were reported
(272). All individuals using opioids and some who are prescribed opioids are at
risk for accidental overdose. Federal, state, and local governments have made
efforts to increase the distribution of naloxone. It is recommended that all
patients who are using opioids have access to FDA-approved parenteral or
intranasal naloxone reversal devices. It is further recommended that peers and
family members of persons using opioids receive training on overdose
identification and instruction on naloxone use. Many states have increased
access to naloxone by removing physician prescribing requirements and
allowing pharmacists to dispense naloxone.
PATIENTS WITH CO-OCCURRING

PSYCHIATRIC DISORDERS
The high rate of co-occurring psychiatric and addictive disorders obligates
treatment providers to equip themselves to address both problems. It can be
difficult to differentiate substance-induced disorders from independent
conditions at intake, but it is noteworthy that symptoms can diminish rapidly
upon initiation of methadone, especially within the first month. Nonetheless,
many patients will remain with psychiatric conditions that need to be addressed.
In an important early study, Woody and colleagues (273) found that low-
severity patients benefited from both drug counseling (focused on current life
problems) and psychotherapy (employing supportive–expressive and cognitive–
behavioral approaches). Patients with high levels of psychiatric symptoms were
lower in all areas of pretreatment functioning, but the addition of psychotherapy
by professionally trained therapists did maximize their improvement in many
areas.
Major depression and persistent depressive disorder (dysthymia) are
common co-occurring disorders in the treatment-seeking population (4,273a)
especially for women (274). Psychosocial stress and the discomforts of
withdrawal may contribute to temporarily low mood as well. Life crises and
depressive symptoms posed a substantial risk of relapse, which lessened for
those who remained in treatment (275).
Anxiety disorders also are common, with symptoms abating with a
combination of an adequate methadone dose and the provision of counseling or
psychotherapy over a period of time (276). Posttraumatic stress disorder (PTSD)
is common in patients receiving methadone, and though it may be associated
with greater drug use disorder severity, PTSD does not necessarily worsen the
outcome of substance use disorder treatment (277). However, both traumatic
events and a resurgence of PTSD symptoms are associated with increased risk of
treatment interruption, despite the fact that patients left treatment (278).
Sleep disorders are often overlooked and appear to be common in those with
psychiatric disorders, chronic pain, and benzodiazepine misuse and in those
whose methadone dose is high (279). Schizophrenia is relatively uncommon in
OUD treatment patients (280), though most programs have some patients with
the disorder. Based on historical references and clinical observations, some
clinicians have proposed that opioids have antipsychotic properties (281),
Clinicians have described a subgroup of patients, who appear calmed and
stabilized by the medication; when their doses drop, they become disorganized.
It is common to find reports of personality disorders, particularly antisocial
personality disorder, in the heroin-using population. Effective treatments are
being developed, even for this difficult group. Ball studied methadone patients
with at least one personality disorder who were receiving two different forms of
psychotherapy and who showed significant reductions in various severity
indicators, including psychiatric symptoms and psychosocial impairment (282).
Although neither heroin nor methadone has been found to be neurotoxic,
several factors among some patients with OUD can increase the likelihood of
cognitive impairment. These include overdose, concomitant hazardous alcohol
use, and traumatic brain injury. Deficits in information processing may also
result in difficulty following instructions and problem solving (283). However,
significant improvement in concentration and executive functions after 8 to 10
weeks of treatment have been reported in both methadone and buprenorphine
groups (284).
A 2016 systematic review of medication use and the risk of vehicle
collisions concluded that both methadone and buprenorphine are among 15
medications associated with increased risk (285). However, a 2014
comprehensive review indicated that although opioids induced some impairment
of driving ability, this is less than other psychotropic agents or drugs of misuse.
These authors note that impulsivity, sensation seeking, low-risk perception,
antisocial behavior, and comorbid psychiatric and neurologic disorders also play
a role. They suggest that the risk for impaired driving is likely less for patients
stabilized on opioid medications (286).
PSYCHOSOCIAL INTERVENTIONS
Psychosocial interventions are considered integral to good treatment in an OTP,
and requirements for this are written into regulations for methadone and
buprenorphine. A 2016 review of psychosocial interventions highlighted the
need for guidelines in matching therapy combinations for individual patients
(287), beyond noting that psychotherapy is useful for patients with moderate
psychiatric severity (288) and that interim or minimal psychosocial treatments
can still benefit patients (289–291). Counseling in OAT has variable availability,
accountability, and quality, although psychosocial care reduces drug use and
improves retention. Counselors act as case managers and may not be prepared
for it, because they range widely in educational level and professional training.
Materials from both the SAMHSA/CSAT and National Institute on Drug Abuse
(NIDA) websites have tried to upgrade counselor training
(www.ncbi.nlm.nih.gov/books) and include motivational enhancement strategies
(292,293) and contingency management (294,295). Buprenorphine-specific
training for counselors is also available (http://www.danyalearningcenter.org).
Matching patients to therapies such as multifamily and parenting therapy have
some guidelines (296) for producing clinically significant improvements across a
variety of domains (297). Overall, a good therapeutic alliance can continue
patient improvement over a period of years (298). Comprehensive services are
also needed (299–305) with monitoring of a close fit between the patient’s needs
and the services delivered (302,306). This system’s level management
(https://www.niatx.net) is essential for agency managers and staff to solve
deficiencies step by step.
OVERSIGHT AND REGULATORY

CHALLENGES
The opioid epidemic will likely continue to be a challenge for at least another
decade. Fortunately, there are new treatment options and beneficial regulatory
changes to bring to bear on the problem. Unfortunately, there are major gaps in
data with no visible prospect of remediation. Buprenorphine was released for
clinical use with the goal of making it widely available. This has been achieved;
however, the absence of requirements for data collection makes it difficult to
know how effective it is in the manner it is currently utilized. Office-based
physicians are not required to create a firm structure for addressing psychosocial
needs or to track progress through regular drug screens or other methods. In the
absence of gathering data on a large scale, we know little about the
characteristics of those taking various medications, whether they are using illicit
drugs of any kind, whether they remain in treatment, and what happens to those
who drop out. Five years is a common standard for evaluating many forms of
treatment, but there appears to be no commitment on the part of the federal
agencies to conducting such studies. Without such research, it is difficult to
advocate for Congress to fund treatment efforts.
In one study, claims data indicate that ~43% of buprenorphine recipients
filled prescriptions for other opioids during their treatment, and 67% filled other
opioids after their treatment. Consistent with other studies, retention was poor;
only 33% continued to fill their prescriptions after 3 months. The data did not
permit analysis of whether other opioids were prescribed for pain, highlighting
the challenge of developing coordination strategies to manage OUD while
managing chronic pain (307).
People who use drugs and dealers are creating new challenges for law
enforcement and public health officials. New preparations, such as fentanyl-
laced heroin, play an increasing role in overdose deaths. It is estimated that 41%
of the heroin-related deaths from 2012 to 2014 involved fentanyl (308). Adding
fentanyl to white powder heroin allows suppliers to cut costs and the price while
creating a serious overdose risk because of the added potency. Since many
people who use drugs who die from a fentanyl overdose do not know they are
ingesting it, surveillance systems and dissemination of information to people
who use drugs are critically important. Fentanyl is found as a drug of deception
in cocaine, methamphetamine, and counterfeit pills. Education has the potential
to deter distribution, sale, and use. Naloxone may require more rapid
administration and perhaps multiple doses than is needed for heroin or other
opioids. Maintaining and expanding access to treatment are crucial to meet this
challenging public health threat.
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CHAPTER 58
Special Issues in Office-Based Opioid
Treatment
Andrew J. Saxon
CHAPTER OUTLINE
Introduction
Epidemiological and Regulatory Issues
Research Issues
Clinical Issues
Conclusions
INTRODUCTION
Current interest in office-based approaches to the treatment of opioid use
disorder springs from a recognition that the numbers and needs of individuals
with this disorder continue to overwhelm the capacity of the traditional,
program-based treatment system. Many such individuals cannot gain access to
opioid maintenance therapy, which is the most effective intervention yet devised
for this disorder (1). Meanwhile, indicators of opioid-related healthcare costs and
criminal justice contacts continue to surge (2,3), as do the number of opioid-
related deaths (4). Many individuals with opioid use disorder also have unique
and serious medical and psychiatric problems that the program-based treatment
system cannot always address and that contribute to morbidity and mortality (1).
Office-based opioid therapy (OBOT) offers one potential avenue and has made
substantial inroads in the drive to ameliorate this unsatisfactory situation.
In addition to referencing research on office-based treatment from France
and the United Kingdom, this chapter reviews some of the historic and
regulatory events that shaped the current treatment system in the United States
and account for some of the ongoing gaps in services for individuals with opioid
use disorder. Office-based treatment effectively fills some of these gaps, in part
because office-based treatment encompasses two distinct treatment paradigms.
First, OBOT offers a less structured, more flexible, and more personalized form
of intervention for patients with opioid use disorder who have succeeded in the
traditional treatment system of opioid agonist clinics licensed by the Center for
Substance Abuse Treatment of the Substance Abuse and Mental Health Services
Administration but who need to continue in pharmacotherapy. Second, OBOT
provides an alternative route of entry into treatment for individuals with opioid
use disorder who, for a variety of reasons, have not had access to adequate
treatment or to reengagement in treatment for individuals who have not achieved
their goals in the traditional treatment system.
A summary of the evidence for the benefits of transferring selected, stable
methadone-treated patients into office-based settings precedes a synopsis of
efforts to apply and evaluate the office-based approach for less stable patients
newly entering treatment. Results of these investigations of office-based
treatment then guide a discussion of clinical issues pertinent to conducting
office-based treatment with patients who have opioid use disorder.
EPIDEMIOLOGICAL AND
REGULATORY ISSUES
During the first few years of the 21st century, the purity of heroin sold in the
United States continued to increase, while the price decreased (5). Heroin-related
emergency department visits have increased from 33,900 in 1990 to 258,482 in
2011 (6). Heroin-related overdose deaths more than tripled between 2010 and
2014 rising to 3.4 per 100,000 individuals in the United States (4). Overdose
accounts for only half the overall observed mortality in people who use heroin,
who exhibit mortality rates 6-20 times greater than those of age-matched
populations (7,8).
A subset of the heroin-using population engages in repeated criminal activity
(9). The Arrestee Drug Abuse Monitoring Program (10) provides urine
toxicology results of 4182 male arrestees in 10 counties around the country.
These data show that, in 2010, rates of adult male arrestees testing positive for
recent opioid use varied around the country from a low of 3% in Charlotte, NC,
to a high of 22% in Portland, OR, and that rates of testing positive increased at
most sites from 2007 to 2010.
The past decades have also seen a surge in the illicit use of and problems
with prescription opioid medications. Emergency department visits related to
nonmedical use of opioid analgesics increased from 168,379 in 2005 to 366,181
in 2011 (11). Large numbers of overdoses on prescription opioids have also been
noted (4). In 2015, 3.78 million people in the United States misused prescription
opioids in the past month (12).
Despite these trends, most individuals with opioid use disorder cannot access
adequate treatment services. In 2014, 357,293 individuals entered treatment for
heroin-related opioid use disorder, but only 28.3% received medication
treatment. Similarly, 132,387 entered treatment for prescription opioid use
disorder, but only 20.7% received medication treatment (13). These data reflect a
circumstance that has been prevalent throughout the past 100 years. However,
these data do not reflect individuals receiving office-based opioid treatment,
which is making medication treatment more widely available.
The mobilization of office-based treatment as a response to this problem
does not represent a true innovation but rather a return to a once commonly used
strategy. Thousands of untreated individuals with opioid use disorder also
worried society in the early part of the 20th century. Before the Harrison
Narcotic Act was enacted in 1914 (see Chapter 26, “Addiction Medicine in
America: Its Birth and Early History (1750-1935) with a Modern Postscript”), no
legal restrictions limited the right of physicians to prescribe opioid medications
for the care of patients considered addicted. Although controversy raged then, as
it does now, about how best to handle individuals with opioid use disorder, many
experts of that generation already had recognized the high likelihood that
patients with opioid use disorder would resume opioid use after enforced
withdrawal. Physicians in many areas of the country thus viewed opioid
addiction as a medical disorder; they advocated and practiced the ongoing
prescribing of opioids from their offices as a reasonable and apparently useful
way to manage the problem.
Most of these physicians conducted this part of their work in a responsible
way. A minority may have allowed their practices to become conduits for
controlled substances out of a profit motive without always providing adequate
medical care. On the basis of a small number of reports of this type of
inappropriate prescribing, concern about the safety and wisdom of prescribing
opioids to individuals with opioid use disorder increased in the medical
profession itself as well as among regulators and the general public. In 1919, the
U.S. Supreme Court ruled that the Harrison Act disallowed such physician
prescribing to individuals with opioid use disorder for “maintenance” purposes
(14). This decision effectively ended the first era of office-based treatment for
opioid addiction.
Such a wholesale shift in policy left patients without access to the opioids on
which they depended. Many municipalities responded by creating publicly
funded and administered opioid maintenance clinics (15). For example, when
New York City experienced one of its waves of heroin addiction after World War
I, a clinic under the auspices of the city health department treated 8000 heroin-
addicted patients with prescribed heroin (16). These pioneer efforts at agonist
pharmacotherapy ended within a few years when the Narcotic Division of the
Federal Prohibition Unit shut down these maintenance clinics as violators of the
Harrison Act (15). Thus, from the 1920s onward, physicians were actively
discouraged from treating heroin-addicted individuals, and indeed, medical
school curricula provided no training to physicians in this regard. In essence,
opioid addiction was reconceptualized as a criminal justice rather than a medical
problem. Convicted violators of federal narcotics laws caused an overload in the
federal penal system, so the Congress established federal narcotics hospitals at
Lexington, KY, and Forth Worth, TX, in the 1930s. Despite high recidivism
rates, these isolated facilities remained the only treatment option for opioid-
addicted individuals until the advent of methadone maintenance 30 years later
(15).
In some respects, the severance of opioid addiction treatment from the
general practice of medicine actually was exaggerated in the 1970s when opioid
agonist therapy, in the form of methadone maintenance, once again was
permitted and, to some extent, promulgated. Federal methadone regulations (21
CFR Part 291) promulgated in 1972, and the Narcotic Addict Treatment Act of
1974 mandated a closed distribution system for methadone, with special
licensing by both federal and state authorities. These regulations effectively
made it illegal for physicians not associated with a licensed program to treat
patients with opioid use disorder with agonist pharmacotherapy in an office
setting. Until 2003, a private physician would have to obtain an additional
registration from the U.S. Drug Enforcement Administration, annual
certification by the U.S. Department of Health and Human Services, and
approval by state drug authorities to provide opioid agonist therapy (16). Only a
small number of physicians around the country have been willing to negotiate
this bureaucratic maze. As a result, the only option for patients who desired
opioid agonist pharmacotherapy was to enroll in a specialized, licensed
methadone treatment program. Once again, most practicing physicians were
deprived of exposure to and experience in treating patients with opioid use
disorder.
The divergence between mainstream medicine and opioid addiction
treatment has had some unfortunate consequences. Opioid addiction causes
considerable medical morbidity as a consequence of drug effects and injection
routes of administration (17). Medical problems common in people who use
illicit opioids include infectious diseases such as pneumonia, tuberculosis,
endocarditis, as well as sexually transmitted diseases (18); soft tissue infections
(19); bone and joint infections (20); central nervous system infections (21); and
viral hepatitis (22), particularly hepatitis C (23). In addition, HIV infection poses
a considerable problem among people who inject drugs (22,24). Noninfectious
problems also typically occur in the lungs (25), the central and peripheral
nervous systems (21), the vascular system (19), and the musculoskeletal system
(19). Licensed opioid agonist treatment programs often lack the resources to
provide comprehensive medical care (16), with the result that comorbid medical
disorders may be unattended, delaying care and driving up its ultimate cost. The
economic burden to society in the United States from prescription opioid misuse
alone was $78.5 billion in 2013 with $28.9 billion of that total consumed by
healthcare costs (2).
Similarly, a high prevalence of psychiatric comorbidity, particularly mood
and anxiety disorders, is seen among patients who are addicted to opioids
(26,27), and licensed programs typically cannot provide the treatment these
conditions require (16).
As the divide between general medical practice and opioid maintenance
treatment is bridged, patients have improved access to simultaneous care for
these serious comorbid medical and psychiatric conditions.
Many potential patients who need and desire opioid maintenance treatment
and are willing to enroll in licensed programs cannot overcome the barriers to
entry. Geography creates an impossible hurdle for some. Two states (North
Dakota and Wyoming) do not offer licensed opioid agonist treatment programs.
In states that do offer such programs, the licensed clinics, by virtue of economic
necessity and neighborhood acceptance, tend to be sited primarily in urban
locations (16,28). Even within larger metropolitan areas, specific neighborhoods
or communities can bar licensed clinics (16,29). A few patients who reside in
states or communities without opioid agonist clinics or in rural areas invest
considerable effort in traveling to other states or cities to obtain treatment; most
who cannot afford the time or cost simply must forgo it (28).
Inadequate treatment capacity creates another barrier for potential patients
who do live in reasonable proximity to a licensed clinic (30). Many clinics have
waiting lists that discourage potential patients from even attempting entry (31).
Many more potential patients lack the financial resources to pay for their
treatment (31). Although OBOT does not necessarily cost less than treatment in
a licensed clinic, insurance companies and managed care organizations
frequently reimburse at least some of the expense of physician office visits,
particularly if comorbid conditions are addressed (30).
Finally, the very nature of licensed opioid maintenance treatment clinics,
with the potential to be recognized and stigmatized by passersby, waiting lines
for medication administration, rigid attendance policies, and lack of privacy,
deters some potential patients (32).
Many of the latter concerns pertain most directly to long-term, stable
patients who have achieved a measure of rehabilitation in opioid maintenance
treatment. Such patients have ceased illicit drug use and, in most cases, have
employment and family responsibilities (30,33). To make their schedules
accommodate frequent clinic visits with waits for medication, to hold up their
travel plans to obtain regulatory approval, and to bring them to a locale where
unstable patients with residual drug use congregate may undermine rather than
support their rehabilitation (30,33). In addition, many of these rehabilitated
patients already have derived maximum benefit from counseling and other
services available at licensed clinics. Moving stable patients out of the restrictive
clinic setting while continuing their maintenance pharmacotherapy would permit
reallocation of clinic resources to patients who most need them.
Three important developments altered the landscape. Since 2001, stable,
long-term patients in licensed opioid treatment programs can have visits to
obtain medication less frequently than once per week. The Children’s Health Act
of 2000, signed into law in October 2000, included a provision waiving the
requirements of the Narcotic Addict Treatment Act to permit qualified
physicians to dispense or prescribe schedule III, IV, or V narcotic drugs or
combinations of such drugs that are approved by the Food and Drug
Administration (FDA) for the treatment of opioid addiction. This change, termed
the Drug Addiction Treatment Act, allows qualified physicians to prescribe
certain opioid agonist medications in an office-based setting. In October 2002,
the FDA approved buprenorphine and buprenorphine + naloxone for the
treatment of Diagnostic and Statistical Manual-IV (DSM-IV) opioid dependence
(now called opioid use disorder in DSM-5). These medications were placed in
schedule III and so are available for use in OBOT.
Clearly, the current U.S. treatment system cannot accommodate all the
individuals with opioid use disorder who want or need treatment. A century ago,
office-based treatment met with some success in the United States. The current
resurrection of office-based treatment has helped to remove geographic, social,
and regulatory barriers for both new and rehabilitated patients and thus make
opioid maintenance treatment more widely available. Because of the divide
between opioid maintenance treatment and general medical practice, some
physician education and training in management of pharmacotherapy for opioid
use disorder have been necessary, have been delivered, and will continue to
occur. Considerable data, described in detail in the subsequent text, offer
instruction to physicians.
RESEARCH ISSUES
Research Related to Stable, Long-Term

Patients in Office-Based Practice
Several investigations have demonstrated the general safety and utility of
transferring patients who have achieved specified degrees of stability through
initial treatment in a licensed methadone clinic into an office-based setting
(Table 58-1). The concept of transferring stable methadone patients to office-
based practice originated with Novick et al. (33–35) of New York City, who
have used this procedure since 1983 and have documented their findings in
several reports over the years.
TABLE 58-1 Studies of Stable Methadone-Treated

Patients Transferred to OBOT
A summary of their work describes outcomes for 158 total patients (36).
Stringent standards were set for patients to participate in the program. Until
1996, patients were required to have completed 5 years of methadone treatment;
this requirement subsequently was reduced to 4 years, though all patients
actually accepted had at least 6 years of methadone treatment. At the time of
entry, all participants had to have at least 3 years without illicit drug use,
excessive alcohol use, or criminal activity. All had to verify employment or other
productive activity. Additional criteria addressed the need for financial,
emotional, and social stability. Patients who met the criteria were transferred
from their methadone programs to the care of internists or family physicians in a
hospital-based practice. The physicians, most of whom had little familiarity with
treating opioid addiction, received specific training from physicians with
experience in methadone agonist treatment. The average methadone dose at
entry was 60 mg/d. Patients attended two office visits in the first month and then
advanced to a monthly reporting and dosing schedule. At each office visit, they
provided a specimen for urine toxicology screening and took a dose of
methadone under observation to confirm tolerance. They received annual
physical examinations from their office-based provider along with routine
medical care as needed.
To remain in compliance with the office-based program, patients had to
avoid methadone misuse or loss, avoid illicit drug use, attend all appointments,
pay fees, and maintain acceptable office comportment. Only 26 patients (16.5%)
ever failed to meet these standards, 15 for uncontrollable use of cocaine, and 11
for other violations. Eighteen of the “failed patients” returned to their clinics of
origin. Patients had a projected median retention time of 13.8 years in office-
based treatment. During the years of this investigation, 12 subjects voluntarily
and successfully tapered off methadone. Of 99 active patients, 27 required dose
increases, while 10 achieved dose reductions.
A retrospective analysis detected several differences between patients for
whom this office-based model was successful. Patients for whom the model of
care was successful were more likely to be married or in stable relationships,
were more likely to have had multiple prior treatment episodes in traditional
methadone programs, and had more total years of treatment in traditional
methadone programs before entering office-based treatment.
A similar, though smaller, uncontrolled trial was conducted in Baltimore by
Schwartz et al. (30). The sample consisted of 21 patients enrolled during a 4-
month period in 1985 and 1986. This program required that patients have at least
5 years’ documented abstinence from illicit drug use in a traditional methadone
program and a record of no alcohol misuse. Patients also were required to have
self-supporting employment and emotional and social stability. Those who used
psychotropic medications for psychiatric disorders were excluded. All patients
transferred to the private office practice were under the care of a single
physician. For the first 6 months, patients visited the office every 2 weeks, at
which time they gave a urine specimen, had a brief interview with the physician,
and received a 14-day supply of methadone. They subsequently advanced to
visits every 28 days and a 28-day supply of medication. Only minor medical
problems were addressed by the primary practitioner, with most healthcare
services delivered by outside referral. Average methadone dose over the course
of the project was 71.4 mg/d. To remain in compliance with the office-based
program, patients had to avoid methadone misuse or loss, have accurate return of
outstanding medication doses during a “callback” procedure, avoid illicit drug or
alcohol use, attend all appointments, and avoid legal problems leading to arrest.
During 12 years of follow-up, six patients (28.6%) failed to comply and
were transferred back to their original methadone program: two for legal
problems, three for positive urine tests, and one for a combination of problems.
Of all urine specimens collected, only 0.5% showed any positive results. Not a
single patient failed any of the 65 random medication callbacks conducted.
A third uncontrolled trial of the transfer of stable clinic-treated patients to an
office-based setting was conducted in Seattle (37). The two programs described
earlier gained permission to provide methadone treatment outside the established
guidelines by obtaining an Investigational New Drug approval by the FDA to
conduct research. The Seattle program was the first to obtain extensive FDA
waivers to establish a clinical program allowing stabilized patients to receive
methadone in a medical setting, with extended take-home privileges. Thirty-one
patients who attended the licensed methadone clinic no more often than three
times a week and who had 12 months of clinical stability (demonstrating
responsibility with take-home medication, no urine drug tests positive for illicit
drugs, consistent clinic attendance, and psychiatric stability) were transferred to
an internal medicine clinic in a public hospital for primary medical care and
methadone treatment. General internal medicine specialists cared for the patients
after attending several training sessions on opioid addiction and agonist therapy.
Ongoing counseling beyond physician visits was not required but was available
through the licensed clinic. Trained pharmacists dispensed the medication
through a satellite hospital pharmacy in the medical clinic.
Patients who demonstrated stability in office-based care could be advanced
to monthly medication pickups. Subjects supplied monthly urine toxicology
specimens and had to comply with periodic medication callbacks. Patients who
required intensive monitoring or treatment could be returned immediately to the
licensed methadone clinic. Twelve-month results showed that 28 of 30 patients
were still in office-based treatment, with 2 patients choosing to leave the
program voluntarily. Only two patients provided any drug-containing urine
toxicology specimens, and 99% of collected specimens were negative.
An additional retrospective study of 127 patients receiving methadone
transferred to an office-based setting had similar positive results (38).
Although the investigations described certainly suggest that most highly
stable patients receiving methadone can safely transfer to office-based care, the
lack of control groups in these open trials precludes conclusions about whether
fewer subjects would deteriorate if they remained in traditional methadone
clinics. A few controlled investigations of stable methadone patients in office-
based practice have been completed. The largest of these controlled trials,
although a very worthwhile study that addressed many of the concerns pertinent
to office-based practice, did not represent, in the strictest sense, a trial of office-
based practice because of the methodology employed. In the study, Senay et al.
(39) worked with a group of 130 patients who had received at least 1 year of
methadone treatment, who had 6 months of negative urine toxicologies, steady
employment or productive activity, no arrests, general program compliance, and
no current legal involvement. Patients were assigned randomly to either an
experimental (two of three subjects) or a control condition (one of three
subjects). The experimental condition consisted of a monthly visit with a
physician; observed ingestion of methadone every 14 days, with 13 take-home
doses for use between visits; three random urine toxicology screens per year; and
random medication callbacks. Patients were required to attend at least one
counseling session and leave one nonrandom urine specimen per month in their
clinic of origin. Thus, the experimental subjects did continue ongoing contact
with their traditional methadone programs, a situation not typical of most office-
based paradigms. The control subjects remained in their clinics of origin for 6
months and then entered the experimental program. The report of this study did
not provide methadone dose levels. Subjects continued in either the experimental
or control conditions if they provided negative urine specimens, paid their fees,
and refrained from criminal activity or lateness. During the first 6 months, 89%
of experimental and 85% of control subjects remained in the program. At 1 year,
73% of both groups remained. Of the patients removed from the program, 70%
were for positive urine specimens, and 30% were for other causes. Removal
rates did not differ by condition. The report of this study does not mention the
results of the medication callbacks. The advantages of this study derive from its
randomized, controlled methodology and from its enrollment of subjects who
had far less time in traditional methadone programs and less stable time than did
the subjects in the studies described earlier by Salsitz et al. (36) or Schwartz et
al. (30). Obviously, subjects of the type in the Senay et al. (39) study comprise a
much larger proportion of typical methadone clinic populations than do the
exceedingly stable patients in the other studies. The disadvantage of the Senay
study resides in the fact that all subjects continued some attendance and
counseling at their clinics of origin. Hence, the study really only demonstrates
that most moderately stable patients receiving methadone can manage
adequately with observed ingestion of medication only once every 14 days and
monthly contact with a physician, but it conveys little about office-based
practice independent of a traditional methadone program.
Two small controlled studies have, however, assessed office-based practice
for stable patients receiving methadone without confounds from ongoing clinic
involvement. In one study (40), 46 patients already receiving methadone agonist
therapy at a licensed treatment program were randomly assigned to be
transferred to office-based treatment with an internal medicine physician (n =
22) or to remain in standard clinic treatment (n = 24). Eligibility requirements
for participants included more than a year of methadone treatment; 1-year
abstinence from use of illicit opiates, as reflected by negative monthly random
urine specimens; no current evidence of dependence on other substances; no
significant medical or psychiatric conditions that could be compromised by the
transfer; a source of legal income; and stable housing. Of note is the fact that
only slightly more than 10% of the clinic’s total population met these criteria,
which clearly are less stringent than those employed in the studies by Salsitz et
al. (36) and Schwartz et al. (30). The average methadone dose for the subjects
assigned to the office-based treatment condition was 69 mg. The average dose
for those assigned to remain in standard clinic treatment was 70 mg. The six
physicians who provided the office-based treatment and their staff members
received training in management of patients on opioid agonist therapy.
Subjects assigned to office-based treatment received a weekly supply of
methadone from the physician’s office. They had an initial 1-hour office visit in
which a history and physical were performed. They subsequently met with their
physician monthly. Subjects assigned to remain in standard clinic treatment came
to the clinic one to three times a week to pick up their methadone. All subjects
provided monthly urine specimens and quarterly hair specimens for
toxicological analysis. If a patient’s urine was positive for opioids or cocaine or
negative for methadone, a repeat urine specimen was obtained within 1 week. If
this repeat specimen also tested positive for opioids or cocaine or negative for
methadone, patients were considered out of compliance with the protocol,
removed from the study, and transferred back to routine care. During a 6-month
follow-up interval, 18% of the office-based subjects and 21% of the standard
clinic subjects violated the study criteria and were transferred back to routine
care. By urinalysis, hair toxicology, or self-report, 55% of office-based and 42%
of standard clinic subjects had evidence of illicit opioid use and 27% and 25%,
respectively, had evidence of cocaine use.
Hair toxicology testing at baseline in this study allowed for some valuable
observations. Though all subjects had submitted 12 consecutive negative
monthly urine specimens before entering the study, hair testing found evidence
of illicit drug use in the preceding 90 days by 44% of the subjects. Though the
failure of monthly urine testing to detect all substance use does not come as a
surprise (41), positive hair testing at baseline did act as a predictor of substance
use during follow-up. Among those with positive hair toxicology at baseline,
90% had evidence of illicit use during follow-up. In contrast, only 20% of those
with negative baseline hair toxicology had such evidence at follow-up.
In another controlled study (42,43), 98 subjects who were receiving
methadone treatment were randomly assigned to one of three conditions: (a)
medication pickup every 28 days in a physician’s office away from the licensed
treatment program; (b) medication pickup every 28 days, with a monthly
physician visit at the licensed treatment clinic; or (c) continued routine clinic
care, with medication pickup once or twice a week at the clinic. Of those
randomly assigned, six declined further participation after receiving their
treatment assignment and were terminated from the study. Eligibility
requirements for participants included continuous methadone treatment and
absence of any positive monthly urine specimens over the preceding 12 months,
full-time employment, and no failed medication recalls or problems handling
medication over the preceding 24 months. About 25% of patients from two
different clinics met these criteria. The average methadone dose was 65 mg/d.
The four physicians who provided the office-based treatment had previous
experience treating patients with methadone agonist therapy. All subjects
received a single 20-minute counseling session per month. The 28-day pickup
subjects received counseling from their physicians. The routine care subjects
received counseling from clinic counselors. All subjects submitted to a monthly
random medication recall procedure. All subjects gave two urine specimens per
month. The 28-day pickup subjects provided a routine, nonrandom specimen at
the time of their scheduled physician visits and also produced a random urine
specimen at the time of the medication recall. The routine care patients gave a
routine random urine specimen once a month, just as did the other clinic
patients, and provided a second random specimen at the time of their medication
recall. An innovative stepped-care counseling intensification procedure was used
so that subjects who exhibited problems such as a positive urine specimen or
failed medication recall could be transferred back to the clinic for five weekly
medication visits until they again attained stability. They would then resume
treatment in their assigned research condition. Treatment retention at 12 months
was 82% for routine clinic care, 79% for clinic-based medical maintenance, and
92% for office-based medical maintenance. Only 12 patients submitted positive
urine specimens over 12 months (9 had one positive, 2 had two positives, and 1
had repeated positive specimens for cocaine and benzodiazepines), while nearly
30% of patients failed at least one medication recall. These problems resulted in
33 subjects (36%) entering intensified counseling. The three groups did not
differ significantly in the likelihood that patients would experience any negative
outcome.
Consideration of the overall data obtained from patients who have achieved
some measure of stability on methadone therapy delivered in a clinic setting
shows fairly convincingly that most can transfer successfully to office-based
care. In addition, in virtually all cases, patients who fail in office-based treatment
because of substance relapse or rule violations can be returned to routine clinic
care to receive intensified counseling and monitoring without undue harm. The
controlled studies also suggest that relapse or other problems in previously stable
patients in office-based practice occur at rates no greater than those of similarly
stable patients who remain in routine clinic care.
Research Related to Patients Entering

Directly into Office-Based Practice
Although policies and attitudes in the United States had, until 2000, steered
practitioners away from the idea of bringing unstable individuals with opioid use
disorder directly into office-based treatment, other countries have, out of
necessity and an innovative spirit, embraced this concept more quickly (Table
58-2).
TABLE 58-2 Studies of Patients Admitted Directly to

Office-Based Opioid Treatment
For example, in Scotland, most patients who receive methadone have it
prescribed in general practitioners’ offices and ingest it in community
pharmacies (44–48). These general practitioners receive training specific to this
endeavor (45). A 1-year follow-up of 204 patients with opioid use disorder who
entered such a paradigm in 1996 has been reported by Hutchinson et al. (45). A
total of 58 general practitioners provided treatment to these patients. The study
report does not specify the frequency or content of office visits, so practitioners
presumably arranged their interventions on an individualized basis. The report
also does not explicitly mention the frequency with which methadone doses
were taken under observation, but it implies that this occurred on a daily or near-
daily basis. Methadone dose levels are reported only for the 50 subjects who
remained in continuous treatment for 12 months and who completed follow-up
interviews. These subjects began at an average dose of 43 mg and increased to
an average dose of 65 mg at 12 months. Follow-up interviews at 12 months were
completed with 119 subjects (58.3%). Predictors of failure at follow-up included
prostitution, unstable living arrangements, higher proportion of drug-using
associates, higher daily drug expenditures, a higher level of benzodiazepine use,
and a higher proportion of income from illegal sources. Among the 119 subjects
followed up, 50 (42.4%) remained continuously on methadone for 12 months, 34
(28.8%) interrupted and then resumed methadone treatment, and 35 stopped
methadone treatment. In the group who stopped treatment, 39% did so because
of imprisonment, 33% did so because they were taking other drugs or
misbehaving in the pharmacy, and 27% left voluntarily because they disliked the
program. In one analysis, the researchers imputed missing data for follow-up
failures by carrying forward their baseline values. In this analysis, daily opioid
injecting for the entire cohort declined from 80% at baseline to 43% at 12
months, the mean daily amount spent on drugs declined from £63 to £38, and the
mean number of acquisitive crimes in the preceding month declined from 18 to
11. Another analysis that examined subjects followed up at 12 months compared
50 subjects who remained continuously on methadone with 57 subjects who
interrupted methadone treatment during the first 6 months. Only 2% of those
who remained continuously on methadone reported daily opioid injecting at 12
months as compared with 21% of those with interrupted treatment. Continuous
treatment subjects were spending a daily mean of £4 on drugs at 12 months,
compared with £16 for those with interrupted treatment. Continuous treatment
subjects committed a mean of three acquisitive crimes in the preceding month,
compared with five for those with interrupted treatment.
England also has had a policy since the 1980s of encouraging individuals
with opioid use disorder to get methadone treatment through office-based
treatment by general practitioners (49). A nonrandomized comparison study
evaluated subjects who began methadone in 1995, either in a specialist drug
clinic (n = 297) or with a general practitioner (n = 155). Training required for
general practitioners was not specifically mentioned. At baseline, the two groups
were similar in illicit drug use except that the specialist clinic group had greater
use of amphetamines. The mean initial methadone dose was 51 mg (standard
deviation [SD] = 18.7) for the general practitioner group and 48 mg (SD = 19.1)
for the specialist clinic group. General practitioners prescribed less than daily
dispensing for 43% of their patients, while specialist clinics allowed less than
daily dispensing for only 25% of their patients. Only 14% of general
practitioners required that methadone administration (at retail pharmacies) be
supervised. Frequency of office visits with general practitioners was not
specified. Follow-up at 6 months was achieved with 76% of the original sample.
At 6 months, 66% of general practitioner patients and 60% of specialized
clinic patients remained in treatment. In both groups, heroin use was reduced, on
average, from more than 19 days per month at baseline to fewer than 10 days per
month at follow-up; there was no significant difference between groups. All
other substance use was reduced significantly and similarly for both groups.
Drug injecting decreased among the general practitioner group from 53% to 41%
and among the specialist clinic group from 66% to 53%. Non–drug-related crime
fell among both groups but significantly more so among the general practitioner
group.
France did not offer agonist pharmacotherapy to individuals with opioid use
disorder until the introduction of methadone at specialist addiction centers in
1995 (50). Shortly thereafter, buprenorphine became available in France for the
treatment of opioid use disorder, and general practitioners, regardless of their
training, gained permission to prescribe it for this indication (50,51). General
practitioners in France can prescribe up to 28 days’ supply of take-home
medications and a maximum daily buprenorphine dose of 16 mg. As of 2004,
about 65,000 patients per year had received buprenorphine in this office-based
paradigm (52). A nonrandomized comparison study examined outcomes for
patients with opioid use disorder in France who were treated with buprenorphine
by general practitioners (n = 32), compared with patients treated with
buprenorphine at specialized addiction centers (n = 37) (50). The general
practitioners had a fixed frequency of consultations, although the report does not
specify the frequency. General practitioners performed urine testing weekly,
required cannabis abstinence, and could arrange psychosocial services but did
not necessarily have such services available. The addiction centers had a variable
frequency of consultations, had no systematic frequency of urine testing, did not
require cannabis abstinence, but had psychosocial services directly available.
Apparently, subjects self-selected their own treatment venues.
The two groups differed at baseline on important variables. The patients
treated in the addiction centers were older, less likely to be employed, had more
polydrug use, experienced many more episodes of overdose, and were more
likely to be injecting heroin. Doses of buprenorphine (5.9 mg/d for the general
practitioner group vs. 6.6 mg/d in the addiction center group) were relatively low
in both groups. Treatment retention at 180 days was ~70% in the general
practitioner group and about 60% in the addiction center group. Addiction
Severity Index scores improved similarly for both groups from baseline to 90
days.
The first U.S. study to evaluate a quasi–office-based approach to individuals
with opioid use disorder just entering treatment also used buprenorphine as an
agonist pharmacotherapeutic agent (53). Potential subjects with other drug or
alcohol addiction, recent cocaine use, or complex medical or psychiatric
comorbidities were excluded. Subjects were assigned randomly to receive 12
weeks of buprenorphine pharmacotherapy, either in a primary care setting or in a
drug treatment setting that typically provided methadone treatment. The primary
care setting was housed in a clinic designed to handle the primary care needs of
people who use substances and patients with psychiatric disorders. Physicians in
the primary care setting relied on a manual-guided clinical management
protocol. Subjects assigned to the primary care setting (n = 23) received an
initial 1-hour visit with a primary care provider, who recorded a substance use
and medical history, created a treatment plan, made a referral to group
psychotherapy, and prescribed buprenorphine. The subjects then saw their
primary care provider in weekly 20-minute sessions. Group therapy conducted
by a primary care nurse practitioner occurred weekly for 50 minutes, with a self-
help focus on promoting abstinence.
Subjects assigned to the drug treatment setting (n = 23) received a standard
set of services, including individualized substance use disorder counseling and
weekly relapse prevention group therapy. In both settings, subjects attended 5
days during week 1, with a buprenorphine dose escalation beginning at 2 mg and
doubling daily until the dose reached 32 mg on day 5. From weeks 2 through 12,
subjects attended clinic three times a week and received observed buprenorphine
doses of 22 mg on Mondays and Wednesdays and 40 mg on Fridays. Thus, this
study avoided prescribing take-home medications. Subjects in both settings also
gave urine specimens three times a week. Patients were terminated from the
study for missing three consecutive medication doses or for failure to attend
group therapy. Successful completion of 12 weeks of treatment was observed for
78% of the subjects in primary care, compared with 52% of the subjects in drug
treatment. Urine specimens were positive for opioids in 63% of urine specimens
provided by primary care subjects, compared with 85% of drug treatment
subjects. Primary care subjects showed a decreasing trend of opioid-positive
specimens over time, whereas drug treatment subjects did not. Roughly a third of
urine specimens in both groups tested positive for cocaine (53).
This study lends some support to the notion that treatment-seeking patients
with opioid use disorder can derive as much benefit from treatment in an office-
based setting as from a drug treatment setting. Nevertheless, the researchers
themselves properly note several aspects of the study design that limit its
applicability to a true office-based setting. The primary care setting in this study
required many more visits and more observed medication administration than
would be practical in a typical office-based practice. The clinic used for the
primary care setting had much more familiarity and expertise with substance-
using patients than would most office-based settings. The study excluded
patients with the medical and psychiatric complications commonly seen in
treatment seekers with opioid use disorder.
Another, much larger U.S. study also examined a quasi–office-based
approach for patients with opioid use disorder just entering treatment (54). This
study differed from the others in that it did not compare an office-based with a
clinic approach but rather compared different medication strategies within a
quasi–office-based setting. In this randomized, double-blind, placebo-controlled,
multicenter trial, 326 subjects were randomly assigned to receive (a)
buprenorphine 16 mg/d, (b) buprenorphine 16 mg + naloxone 4 mg/d, or (c)
placebo. Medication was administered in office-based settings affiliated with
Veterans Affairs Medical Centers. Subjects received their doses 5 days a week,
with take-home medications given for weekends and holidays. The trial was
terminated early because of the demonstrated efficacy of buprenorphine +
naloxone compared with placebo. Subjects treated with either buprenorphine
alone or buprenorphine + naloxone had a greater proportion of urine specimens
that were negative for opiates than did the subjects given placebo. The rate of
adverse events was manageable and comparable between the two active
treatments.
The largest study yet conducted of office-based treatment, A Multicenter
Safety Trial of Buprenorphine + Naloxone for the Treatment of Opiate
Dependence, consisted of an uncontrolled, naturalistic investigation that
examined outcomes for 582 individuals with opioid use disorder newly entering
office-based treatment. Patients were not excluded for psychiatric or medical
problems (other than pregnancy, because buprenorphine + naloxone is not
approved for use in pregnant patients), as long as the treating physician could
manage the problems on her or his own or by appropriate referral. Patients were
treated by 38 physicians in seven states with buprenorphine + naloxone, in doses
ranging from 2 mg/0.5 mg to 24 mg/6 mg/d. Medications were dispensed by
institutional and community pharmacies. Physicians and pharmacists involved in
the study received at least 8 hours of training in the pharmacology of
buprenorphine + naloxone and issues pertinent to office-based treatment of
opioid addiction. Treatment lasted up to a year. Patients were seen by the
physicians at least twice in the first week of treatment, at least weekly during
weeks 2 through 12 of treatment, at least biweekly from weeks 13 to 26, and
monthly thereafter until week 52. For stable patients, medication dispensing
followed a pattern similar to the office visits, so that in the final 6 months of
treatment, patients could have monthly medication pickups. Urine toxicology
screens were obtained onsite at each office visit. Relapse prevention counseling
was available and encouraged but not required. Patients who became stable early
in treatment had the option to taper the dose of buprenorphine + naloxone
between weeks 7 and 9 and to complete treatment at that time.
The majority of patients (97.6%) were successfully inducted with the
buprenorphine–naloxone combination. Most patients received 4 mg (22%), 8 mg
(33%), or 16 mg (18%) on their first day. The most common maintenance doses
prescribed to patients were 8 mg (11%), 16 mg (26%), and 24 mg (29%). The
16-week completion/retention rate was 362 (62%), with 189 patients (32.5%)
completing either a supervised withdrawal or 52 full weeks of treatment. Patients
demonstrated a significant decrease in percent of opioid-positive urines over
time. There was significant improvement in composite scores for drug, legal, and
family/social domains of the Addiction Severity Index. A significant reduction in
HIV risk behavior was also seen (R. Walsh, personal communication, 2007).
Four subsequent smaller uncontrolled studies of patients treated for opioid use
disorder with buprenorphine + naloxone showed outcomes quite similar to those
found in the multicenter safety study (55–58).
As mandated by the Drug Addiction Treatment Act, the Substance Abuse
and Mental Health Services Administration conducted a 3-year evaluation of the
impact of buprenorphine availability between 2002 and 2005 (59). Among the
data sources used for this evaluation were surveys of 959 addiction medicine
specialists (80% response rate), surveys of 1837 physicians who had obtained a
waiver to prescribe buprenorphine (86% response rate), and telephone interviews
with 433 buprenorphine-treated patients recruited through prescribing
physicians’ offices or clinics. The results showed that about half the patients
receiving buprenorphine had never previously received opioid maintenance
treatment. More than half the patients surveyed did not use heroin and were
addicted to prescription opioids. Both the patients and the physicians
overwhelmingly believed that buprenorphine was effective. At 6 months after
treatment initiation, more than 70% of patients remained in treatment or had
completed treatment, and 81% were abstinent from nonprescribed opioids.
Increases in employment and decreases in criminal activity occurred among the
patient group. Opioid maintenance treatment became available in geographic
locations previously not served.
All of these early evaluations of direct entry to office-based treatment for
opioid addiction support its viability as a treatment option and show its
acceptance by patients, physicians, and pharmacists. Treatment retention in these
office-based investigations did not fall markedly below—nor did illicit opioid
use rise strikingly above—rates reported in recent clinic-based investigations of
opioid maintenance treatment, even though the European studies discussed here
used doses of agonist medications that currently would be considered less than
optimal.
Recent years have witnessed a considerable increase in reports in the
literature regarding office-based treatment for opioid addiction with
buprenorphine. Five will be highlighted here because of data they provide on
longer-term outcomes, on effects of this intervention in impoverished
populations, on individuals with co-occurring opioid use disorder and HIV
infection, and on the impact of additional behavioral treatment given in addition
to basic physician management.
One study of longer-term outcomes arose as an extension of a randomized
controlled trial (60). The controlled trial enrolled and randomized 166 patients to
one of three treatments over 24 weeks: (a) standard medical management with
once weekly buprenorphine + naloxone dispensing, (b) standard medical
management with thrice weekly buprenorphine + naloxone dispensing, and (c)
enhanced medical management with thrice weekly buprenorphine + naloxone
dispensing. Standard medical management involved brief, manual-guided,
medically focused counseling (20 minutes); enhanced management used similar
techniques, but each session was extended (45 minutes). The mean maintenance
buprenorphine dose was 17.5 mg. All three treatments had statistically
indistinguishable outcomes and so showed no advantage for extended counseling
or more frequent buprenorphine + naloxone dispensing. Of the 166 patients
randomized in the trial, 53 (32%) achieved at least 9 consecutive weeks free of
illicit opioid use. These patients were enrolled in a long-term study (61). Thirty-
seven and a half percent of patients remained in treatment for at least 2 years
beyond the original 24 weeks, and 24.5 remained 3 years or longer. Of 1106
urine toxicology specimens provided, 91% were negative for illicit opioids.
A second study of longer-term outcomes included 176 patients with opioid
use disorder from both high and low socioeconomic status started on
buprenorphine + naloxone in the office setting with buprenorphine doses of 12-
16 mg/d, although all were also enrolled in intensive outpatient treatment (62).
Data were collected via retrospective chart review and cross-sectional phone
interviews conducted 18-42 months after starting the medication. Among the 110
patients (67%) who completed the interview, 77% remained continuously on
buprenorphine + naloxone. Patients who continued buprenorphine + naloxone
were significantly less likely to have used heroin or any substance and to be
employed at both baseline and follow-up. High socioeconomic status patients
were more likely to be employed at baseline but not at follow-up. Low
socioeconomic status patients were more likely to remain continuously on
buprenorphine + naloxone but also more likely to have substance use at follow-
up.
An examination of 408 opioid-addicted patients treated with buprenorphine
+ naloxone at doses of 8 mg/2 mg/d or 16 mg/4 mg/d in a primary care setting
using nurse care managers showed that of 382 who could be evaluated, 187
(49%) remained successfully in treatment for 1 year, and 9 (2.4%) were stable
for at least 6 months and successfully tapered off medication (63). Among those
who completed 1 year, 91% were no longer using opioids or cocaine based upon
urine toxicology testing. Predictors of success in a multivariate analysis were
white race, older age, and prior nonprescribed use of buprenorphine.
Among 303 patients with opioid use disorder and HIV infection treated in
HIV primary care clinics with buprenorphine + naloxone at a median dose
(buprenorphine) of 16 mg/d over 1 year in a prospective, multisite, clinical
demonstration project, 49% remained on buprenorphine + naloxone for the
entire year (64). Rates of illicit drug use decreased from 84% at baseline to 42%
among patients retained for the full year. This study demonstrates both the
feasibility and effectiveness of integrating office-based opioid treatment into
HIV care.
A question often arises concerning how much behavioral or psychosocial
intervention is needed in addition to basic physician office management for
patients receiving buprenorphine for opioid use disorder. To address this point,
141 such patients treated in a primary care clinic were randomly assigned to
receive either physician management alone or physician management with an
added 12-week course of manual-guided cognitive–behavioral treatment for
substance use disorders (65). Illicit opioid use decreased significantly and
equivalently in both groups and both had equivalent study retention over 24
weeks. Two other studies, though not conducted in office-based settings, found
similarly that the addition of drug counseling (66) or the addition of cognitive–
behavioral therapy and/or contingency management (67) to physician
management alone did not produce superior outcomes. Thus, current evidence
suggests that while adding behavioral interventions to physician management of
opioid use disorder with buprenorphine may have benefit for unmeasured
outcomes such as interpersonal functioning or promoting productive activities, it
is unlikely to have much additional effect on reduction of illicit opioid use or
treatment retention.
Whether patients in office-based treatment should be maintained on
medication or tapered is another issue that frequently comes up. A recent study
examined this topic by randomly assigning 113 patients with DSM-IV
prescription opioid dependence to 14 weeks of buprenorphine maintenance or 6
weeks of stabilization followed by a 3-week taper and the offer of naltrexone
treatment. Patients in the maintenance condition had far less illicit opioid use
and much greater rates of completing the 14-week study (68). Another study, not
conducted in an office-based setting, also found very low success rates with a
buprenorphine taper (66). Therefore, our best current evidence argues against
initiating a buprenorphine taper at least in the first several months of the
treatment process.
CLINICAL ISSUES
The totality of clinical experience with office-based treatment has increased
considerably in the past few years, and the body of evidence reviewed
previously encourages some synthesis of relevant ideas and recommendations
related to clinical practice in an office setting. Again, it makes sense to divide
this discussion into two segments: one most pertinent to care of long-term, stable
patients who are transferred from a licensed program to office-based care and
one focused on management of patients who are admitted directly to an office-
based setting.
Patient assessment and appropriate selection of patients for transfer from
clinic-based to office-based care obviously are key elements of this paradigm. A
comparison of the various studies discussed earlier gives rise to the expected
impression that more stringent selection criteria with more required time and
stability in clinic-based treatment lead to better success after transfer to office-
based treatment. When several years of treatment and stability are required
(31,36), patients exhibit no illicit opioid use and minimal other substance use
and most remain in the protocol for many years. Within the group of subjects in
the study by Salsitz et al. (36), more episodes of methadone treatment and longer
time in treatment were associated with a greater likelihood of a good outcome
after transfer to office-based care. When less stringent selection criteria are used
(40,69), illicit drug use is more likely to manifest in the office-based setting. The
hair toxicology performed in the Connecticut study (40) also provides insights
into this issue. Hair testing detected illicit substance use for some subjects who
were believed by their program to be substance-free on the basis of monthly
urine screens. Positive hair testing at baseline in that study clearly predicted
substance use during the experimental paradigm for subjects in either office-
based or standard clinic care. Because hair testing remains unavailable in most
clinical settings, an alternative might be to obtain weekly or more frequent urine
screens for some period before the anticipated transfer of any apparently stable
patient from a licensed clinic to office-based care.
How thoroughly to assess and how stringently to screen patients for potential
transfer to office-based care also depend on how much illicit substance use
would be tolerated in the office-based setting. The programs thus far reported in
the literature and reviewed here tolerated very little use before initiating
protective transfer of the patient back to standard clinic care. In view of the fact
that patients in office-based methadone treatment may have substantial quantities
of take-home methadone doses in their possession, this conservative approach
toward illicit drug use makes sense. Safety concerns would dictate that patients
who are using illicit drugs should not have any (or have only a negligible supply
of) take-home methadone to minimize the potential for overdose. Also, patients
who use illicit drugs may pose a greater risk of diverting methadone to raise cash
to buy drugs. Nevertheless, the controlled studies indicate that substance use did
not differ on the basis of treatment in office-based versus standard clinic care
(40).
What remains unknown is whether patients transferred to office-based care
who experience more than a few brief episodes of substance use will continue to
deteriorate in office-based care and need protective transfer back to standard
clinic care or whether such relapses could be contained as effectively within the
office-based setting, presuming a practical mechanism exists to limit the number
of take-home doses of methadone provided until stability is regained. The report
by Salsitz et al. (36) described the need for termination of 15 patients with
serious misuse of cocaine who could not be treated within private practice, but it
does not specify what measures might be taken within an office-based setting to
address this type of problem. The stepped care intensification procedure used in
the study by King et al. (42) offered one model for handling instability in the
office-based setting that does not preclude rapid return to office-based care.
Future studies could help to answer this question through controlled trials that
randomly assign office-based patients undergoing a substance use relapse either
to stay in office-based care or to receive protective transfer back to standard
clinic care.
Further, office-based practitioners no doubt vary in their ability to tolerate
and manage relapse. Some may feel very uncomfortable and immediately wish
to transfer the patient back to standard clinical care, while others may prefer to
intensify services in other ways, as through an increased number of office visits,
a referral to counseling or self-help groups, or an increase in the methadone
dose.
Concerns about relapse lead directly to a consideration of techniques for
monitoring stable patients in office-based practice. All the studies described used
urine testing, which would be a common practice in licensed agonist treatment
clinics. With the exception of the study by Senay et al. (39), these studies
typically tested urine specimens at least monthly, often in a nonrandom fashion.
In the study by Fiellin et al. (40), subjects who provided a specimen that was
positive for drugs were required to give another specimen within the following
week. The study by King et al. (42) used a monthly, random medication callback
schedule that also required subjects to give a random urine specimen. Rates of
illicit drug use were lower in this study than in the study by Fiellin et al. (40),
even though the subject populations appear to be relatively similar. Despite the
dangers of comparing results across different studies, these observations lead to
speculation that the random nature of the callback procedures in the King et al.
(42) study may have deterred some illicit drug use. Although the regular and
frequent callback procedure used in that study might prove somewhat
cumbersome in a purely clinical setting, the data argue for physicians who
provide opioid maintenance treatment in an office-based setting to institute some
type of callback procedure. The office-based subjects in the King et al. (42)
study were highly satisfied with their treatment, even though the callback
procedures meant that they had to visit their physician’s office twice rather than
once a month. A callback procedure obviously also helps to minimize the risk of
inappropriate or excessive medication use or diversion.
A monitoring plan that would be practical in an office-based setting would
involve monthly nonrandom urine specimens at the time of scheduled office
visits; a few unscheduled callbacks per year, with medication checks and
provision of random urine specimens; and a very quick callback after any
positive urine specimen to obtain a repeat specimen within a few days. The latter
part of the plan dictates that the physician must use a toxicology laboratory with
a rapid turnaround time and must remain vigilant and act on positive test results
as soon as they are received from the lab. Alternatively, with the technology to
conduct onsite urine testing now readily available, an office setting with that
capacity could detect illicit drug use at the time of the office visit. A more
frequent medication pickup schedule could be instituted immediately, along with
plans to return for repeat urine monitoring.
The clinical management of methadone pharmacotherapy clearly
encompasses another major component of office-based treatment for transferred
patients. A substantial number of subjects in the investigation by Salsitz et al.
(36) required methadone dose changes. Physicians who treat patients with
methadone in office-based practice need to remain alert to the need for
alterations in medication dose. Methadone plasma concentrations can change
over time in response to a variety of somewhat unpredictable environmental
factors, and such changes could lead to variations in clinical medication effects
(69,70). Thus, physicians should frequently inquire about symptoms such as
rhinorrhea, lacrimation, chills, nausea, diarrhea, muscle aches, and insomnia and
assess whether these symptoms could be related to opioid withdrawal. They
should query patients about thoughts of drug use or cravings. If such symptoms
are occurring, an increase in the methadone dose should be given serious
consideration. Similarly, physicians should ask about possible methadone side
effects (such as constipation, excess sedation, or lowered libido) that may
suggest the need for a reduction in methadone dose. In the absence of serious
side effects or serious risk of relapse to drug use, the patient’s wishes about dose
changes often serve as the best guide to clinical decision-making (71).
Psychosocial interventions form another potentially valuable element of
office-based treatment for transferred patients. It would be expected, in general,
that such interventions would be brief and might be minimal or unnecessary for
the highly stable, long-term patients seen in the studies by Salsitz et al. (36) and
Schwartz et al. (30). In the context of an office visit, it would be desirable for the
physician to ask about the patient’s drug and alcohol use and cravings; how the
patient is doing at work and/or with family or child care responsibilities,
financial and housing circumstances; about psychiatric and medical status; and
about use of leisure time. In most cases, long-term patients will indicate in a few
words that they have maintained stability in these areas of their lives. In the
event that a patient acknowledges some problem or added stress, a few moments
to delineate the scope of the difficulty, express concern and empathy, and
provide support, advice, and encouragement may suffice to assist the patient in
coping with mild or moderate distress. If the problem seems more severe, the
office-based physician must either arrange more frequent sessions with the
patient or have ready access to referral to counseling resources. Some of the
office-based paradigms described earlier (37,42) had ongoing arrangements for
temporary intensification of counseling services at the original licensed
treatment program.
The clinical management of unstable, patients with opioid use disorder
newly entering office-based treatment poses some challenges that overlap those
of already stabilized clinic patients but also some that are distinct. Patients who
enter directly into office-based care exhibit marked reductions in substance use,
risk behavior, and criminality; also, they have higher rates of dropout and drug
use than do stable patients. Even in the study by O’Connor et al. (53), which
excluded subjects with recent cocaine use or serious psychiatric or medical
problems, rates of dropout and substance use were substantial. With the
exception of that study, most investigations of direct entry into office-based
treatment have applied no exclusions to admission, so little direct scientific
information exists to guide patient selection. To a great extent, then, patient
selection for direct entry into office-based treatment must rely on the specific
areas of expertise and clinical skills of the treating physician. Through thorough
assessment, including a complete history and physical examination, the
physician should ascertain whether he or she can comfortably manage—either
by direct care or by adequate referral networks—the combination of substance
use problems, general medical problems, psychiatric problems, and life crises
likely to arise in the treatment of each patient. Physicians should exercise
caution and refer patients who are not good candidates for their practice settings
to licensed treatment programs. Although the current evidence suggests that
many patients who enter directly into office-based opioid maintenance treatment
have a smooth course, many certainly remain unstable for some time. Physicians
who accept patients directly into office-based treatment will have to be able to
tolerate and deal with some serious and unexpected clinical events.
As with stable, transferred patients, appropriate monitoring strategies will
help the physician to stabilize patients newly entering office-based treatment.
Again, no solid scientific data are available to guide precise techniques or
monitoring schedules. Urine toxicology testing and periodic medication
callbacks, coupled with regular clinical evaluation, likely will continue to serve
as the mainstays of monitoring.
Medication-dispensing schedules allow another method of managing
instability. For transferred, stable patients, weekly or more frequent dispensing
schedules make no sense because such patients could obtain equivalent
schedules at licensed clinics. For newly entering patients, conversely, tight
control of medication dispensing, when practical, likely enhances the patient’s
progress toward stability. Buprenorphine and buprenorphine + naloxone are the
only opioid maintenance medications approved for the treatment of patients with
opioid use disorder directly entering office-based care in the United States.
Although daily observation of medication ingestion would not be practical in
most office-based settings, buprenorphine can be administered effectively three
times a week (53), a schedule that probably is feasible in some office-based
settings and/or their affiliated community pharmacies.
Monitoring and dispensing schedules will vary much more for newly
entering patients, with more intensity of services expected initially, later
decreasing as indicators of stability appear. Such indicators would include
generally compliant behavior; regular, timely attendance at scheduled office
visits; successful compliance with medication callbacks; negative urine
toxicology tests; productive use of time; supportive interpersonal relationships;
and the absence of criminal justice involvement. As such signs of stability
appear, medication dispensing can be liberalized from three times a week to once
a week, biweekly, or monthly, with an appropriate number of take-home doses.
The frequency of scheduled office visits, urine testing, and medication callbacks
can be adjusted in a similar fashion. If signs of instability reappear, any or all of
these monitoring techniques can be readjusted for greater frequency.
As in the treatment of stable, transferred patients, careful pharmacotherapy
of newly entering patients can contribute to their stability. The physician needs
considerable skill to prescribe buprenorphine, particularly in view of its potential
to precipitate opioid withdrawal during induction of patients with high levels of
physical dependence (72–74). This characteristic of buprenorphine generally
dictates initiation of pharmacotherapy at low doses, followed by dose escalation
as soon as the patient demonstrates medication tolerance. Throughout the course
of treatment, as in the care of transferred patients, the physician will need to be
alert to the signs and symptoms described earlier and be ready to adjust the dose.
The potential for medication diversion plays into decisions about medication
dose and frequency of dispensing. Certainly, diversion poses a danger to the
community by increasing the supply of illicit opioids. In addition, diversion by a
patient undermines and endangers the patient’s efforts toward achieving a stable
recovery from opioid use disorder. The presence of illicit methadone and
buprenorphine in the community lets us know that some diversion is indeed
occurring. Scant firm data exist on the frequency or the patient characteristics
and behaviors associated with diversion, though self-reports suggest that
18%-28% of patients in treatment with methadone or buprenorphine have
diverted or received diverted medications (75). Failing a medication callback or
request for early refills because of purported lost or stolen medication offers
some obvious warning signs. A negative urine test for methadone metabolite or
buprenorphine or its metabolite norbuprenorphine also suggests possible
diversion. Other more subtle but certainly not pathognomonic signs might be a
sudden unexplained increase in disposable income or a sudden request for a dose
increase in a previously stable patient without an apparent explanation for
instability. Physicians can deal with the risk of diversion first by exercising
preventive measures. They should convey to patients at the outset of treatment,
preferably in a written agreement, that being prescribed opioid medications
entails a lot of responsibility and that diversion will not be tolerated. Loss of
take-home medication or even discontinuation of treatment could be a
consequence for diversion. Faced with these strictures, those patients who might
actually consider diversion will desist for fear of losing their treatment.
Medication callbacks, as noted earlier, also serve as a bulwark against diversion.
If patients know that they will have to account for all outstanding medication,
diversion will be deterred. If diversion is suspected, a callback should be
implemented. If the patient fails the callback, appropriate interventions depend
on the specific circumstances of the patient and the practice. At the very least,
the amount of medication dispensed at any one time should be drastically
reduced. Some physicians might want to consider discontinuation of office-
based treatment and referral to a licensed opioid treatment program if available.
Repeated episodes of diversion clearly indicate that office-based treatment is not
an appropriate setting and argue for transfer to a more structured, licensed
program.
Psychosocial treatments may be even more important to patients who are
newly entering office-based treatment than to stable patients who already have
received regular counseling at a licensed program. Scant scientific data are
available to provide reliable instruction as to the optimal modality or frequency
of psychosocial treatments for these patients. The uncontrolled studies conducted
in Britain did not evaluate the variety of psychosocial treatments prescribed by
physicians. The study by O’Connor et al. (53) used weekly physician visits and
weekly group therapy—an intensity of psychosocial services that might not be
available or reimbursable in most clinical settings. Studies of various intensities
of psychosocial services in licensed methadone programs (76–78) do offer some
illumination on this point: patients who receive minimal psychosocial services
do not fare as well as do those who receive moderate or high levels of services;
however, the lower cost-effectiveness of more intensive services may nullify any
slight advantage they hold over moderate services (78,79). One controlled study
of the efficacy of weekly extended medical management counseling (45-minute
sessions) compared to weekly standard medical management counseling (20-
minute sessions) added to buprenorphine + naloxone treatment, as noted above,
found no advantage of the extended counseling (60). As noted above, recent
evidence suggests that high-quality medical management may be sufficient for
many newly entering patients (65–67). For patients who fail to achieve stability
additional psychosocial services then could be titrated to the response of each
individual patient. One convenient way to provide free psychosocial services is
by referral to mutual help groups in the community. Sometimes such groups are
not supportive of pharmacotherapy for opioid use disorder, so it behooves the
physician to assist patients in locating groups that will not stigmatize them for
taking appropriately prescribed medications.
Many of the studies summarized here used some form of brief physician
training before the physician engaged in office-based care of opioid-dependent
patients. As with many aspects of OBOT, little empirical evidence exists to
specify the optimal training method. Practicing physicians have limited amounts
of time in their schedules for training, so a brief course makes sense. At present,
physicians in the United States are eligible to practice office-based treatment of
opioid addiction on completion of 8 hours of formal training and physician
assistants and nurse practitioners are eligible with 24 hours of formal training.
Expert consensus suggests that appropriate training should consist of most of the
following topics: (a) overview of opioid use disorder and rationale for agonist
treatment; (b) legislation permitting office-based treatment; (c) general opioid
pharmacology; (d) pharmacology of buprenorphine and buprenorphine +
naloxone; (v) efficacy and safety of buprenorphine; (e) clinical use of
buprenorphine, including induction, stabilization, and withdrawal; (f) patient
assessment and selection; (g) office management, including treatment
agreements, urine testing, record keeping, and confidentiality; (h) co-occurring
psychiatric and medical disorders; (i) psychosocial treatments; and (j) special
populations, including adolescents, pregnancy, and patients with pain.
CONCLUSIONS
Patients with opioid use disorder clearly need medical treatment, which has not
always been readily available. In recent decades, the system has tried to meet the
challenge by providing opioid maintenance pharmacotherapy at licensed
treatment programs. This approach has greatly improved the outcomes and lives
of many patients but has failed to accommodate many others because of
inadequate capacity and because, for some individuals, attendance at such a
program creates undue hardships. Good scientific data now show that transfer of
patients who have 1 or 2 years of demonstrated stability in a licensed methadone
program to office-based care leads to outcomes comparable to those obtained if
the patients had continued at a licensed clinic. If such patients become unstable
in office-based care, they can be transferred safely back to clinic care.
Many such patients prefer office-based care and have more time for
productive activities when receiving treatment in an office setting. Moreover,
transferring such patients to office-based care opens treatment slots in licensed
opioid treatment programs to previously untreated patients. Now that many
thousands of patients have been treated in office settings, the appropriate
management techniques (including patient selection, monitoring, and
pharmacotherapy) have been reasonably well established.
Studies of office-based care of patients with opioid use disorder newly
entering treatment likewise suggest that such care is reasonable for many such
patients and that their short-term outcomes appear nearly equivalent to those
achieved with similar patients in traditional licensed programs. More can still be
learned about optimal management techniques in office-based treatment via
additional rigorous research.
As more knowledge has accrued about office-based treatment of opioid
addiction, and as it has become a more widespread practice, some positive
“ripple effects” have ensued. The “treatment gap” has narrowed somewhat as
more patients who live in a variety of locations and have varying needs have
gained access to opioid agonist treatment. The medical and addiction treatment
systems have taken small steps toward reintegration. With these efforts, ideally
medical and psychiatric comorbidities will be attended to more fully, and
physicians may become more willing to address substance use problems in
addition to opioid use disorder. Society in general may benefit from reductions
in crime and its associated costs, from an increased engagement in the workforce
by previously unemployable individuals, and, possibly, from an overall decline
in healthcare expenditures shifted from acute care for the medical sequelae of
untreated opioid use disorder.
Sidebar Concerning Veterans and Office-

Based Treatment of Opioid Use Disorder
Office-based treatment with buprenorphine has seen rapid uptake for veterans
with opioid use disorder treated by the Department of Veterans Affairs. The
number of veterans receiving buprenorphine increased from 300 at 27 facilities
in 2004 to 6147 in 118 facilities in 2010 (80). Unfortunately, consistent with the
nationwide epidemic of opioid use disorder described in this chapter, the
number of veterans with opioid use disorder receiving care at the VA increased
by 45% during that same interval so that the proportion of veterans with opioid
use disorder getting opioid agonist treatment had not gone above 27% (80). In
2016, the number of VA patients receiving buprenorphine rose again to 12,525
but still represented only 20.9% of those diagnosed with opioid use disorder.
An additional 4045 (6.8% of those with opioid use disorder) received
naltrexone. Thus, a treatment gap still exists in the VA, as it does elsewhere,
pointing to the need for creating training opportunities and incentives for more
widespread implementation of buprenorphine treatment, especially since VA
data suggest that office-based treatment with buprenorphine may be one way to
meet the treatment needs of the growing population of opioid use disorder
patients (80).
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CHAPTER 59
Pharmacological Treatment of
Stimulant Use Disorders
David A. Gorelick
CHAPTER OUTLINE
Introduction
Cocaine Use Disorder
Choice of Medication
Amphetamine Use Disorder
Special Treatment Situations
Future Prospects
Conclusions
INTRODUCTION
Stimulants such as cocaine and amphetamines are the second most widely used
illegal drugs, surpassed only by cannabis. In 2014, an estimated 18.2 million
people (15-64 years old) worldwide used cocaine, a prevalence of 0.38%; and an
estimated 35.6 million people used amphetamines or prescription stimulants for
nonmedical purposes, a prevalence of 0.8% (1). In the United States in 2015, an
estimated 2.2 million people (12 years and older) met Diagnostic and Statistical
Manual, Fifth Edition (DSM-5) criteria for stimulant use disorder (equivalent to
abuse or dependence in DSM-IV) (2), a prevalence of 0.3% (3). About 40% used
cocaine; the remainder used amphetamines or prescription stimulants for
nonmedical purposes. In 2013, 242 000 patients reporting cocaine,
amphetamines, or other stimulants as the primary drug that they used were
admitted to publicly funded and/or licensed addiction treatment programs in the
United States (4). Despite this clinical need, there is no well-established, broadly
effective pharmacotherapy for stimulant use disorder. Both clinical interest and
scientific interest in pharmacological treatment continue to be stimulated by the
often disappointingly low success rates and short duration of efficacy of current
psychosocial treatments (5).
This chapter reviews the current state of pharmacological treatment for
stimulant use disorder, including choice of medication and medications for use in
special treatment situations, such as patients with mixed addiction or psychiatric
comorbidities. Emphasis is given to the use of medications in clinical practice,
rather than to laboratory studies or preclinical pharmacology. (For more
information about the pharmacology of stimulants, see Section 2, Chapter 12 in
this text.)
More of the clinical and clinical research literature deals with cocaine than
with amphetamines, so these two classes of stimulants are considered separately.
There is very little literature on the pharmacological treatment of other stimulant
use disorders such as methylphenidate and synthetic cathinones (“bath salts”).
The extent to which findings related to cocaine can be extrapolated to other
stimulants remains unknown.
COCAINE USE DISORDER
Goals of Treatment
The goals of pharmacological treatment of cocaine use disorder are the same as
for any other treatment modality, that is, to help patients abstain from cocaine
use and regain control of their lives. The behavioral mechanisms by which
medication achieves these goals are poorly understood and can vary across
patients and medications. In theory, medication could shift the balance of
reinforcement away from cocaine taking in favor of other behaviors through
several mechanisms:
By reducing or eliminating the positive reinforcement from using cocaine

(eg, by reducing the euphoria or “high”)
By reducing or eliminating a subjective state (such as “craving”) that
predisposes to taking cocaine
By reducing or eliminating negative reinforcement from cocaine
withdrawal (as by reducing withdrawal-associated dysphoria)
By making cocaine use aversive
By increasing the positive reinforcement obtained from non–cocaine-taking
behaviors
Currently available medications are considered to act by one or more of the first
three mechanisms, and these mechanisms are the focus of research in medication
development. No current research addresses the fourth mechanism (which would
be analogous to the use of disulfiram in treating alcohol use disorder). The fifth
mechanism is crucial to successful treatment because it ensures that other
behaviors are reinforced to replace cocaine use as the latter is extinguished, but
such medications do not exist. In current practice, this mechanism is engaged by
psychosocial interventions that address issues such as vocational rehabilitation,
the patient’s social network, and use of leisure time.
Because of the importance of this mechanism, as well as other factors such
as medication adherence, medication almost never is used without some
psychosocial treatment component. Few controlled clinical trials explicitly
compare the efficacy of medication use with varying (or no) psychosocial
treatments (6,7), so the relative contributions of pharmacological and
psychosocial treatments are largely unknown. The type, intensity, and duration
of psychosocial treatment that should accompany pharmacological treatment are
questions with little data to guide clinical decision-making. At a minimum, one
would expect that addressing psychosocial factors that influence medication
adherence would improve treatment outcome.
Pharmacological Mechanisms
At least four pharmacological approaches are potentially useful in the treatment
of cocaine use disorder (8). These approaches are (a) a cross-tolerant stimulant
(analogous to methadone or buprenorphine treatment of opioid use disorder), (b)
an antagonist medication that blocks the binding of cocaine at its site of action
(true pharmacological antagonism, analogous to naltrexone treatment of opioid
use disorder), (c) a medication that functionally antagonizes the effects of
cocaine (as by reducing the reinforcing effects of or craving for cocaine), and (d)
alteration of cocaine pharmacokinetics so that less drug reaches or remains at its
site(s) of action in the brain.
No medication currently is approved by the U.S. Food and Drug
Administration (FDA) or any other national regulatory authority for the
treatment of stimulant use disorder because no medication has met the
scientifically rigorous standard of consistent, statistically significant efficacy in
replicated, large controlled clinical trials. Most current clinical and research
attention focuses on reducing or blocking cocaine’s actions, either directly at its
neuronal binding site (true pharmacological antagonism) or indirectly by
otherwise reducing its reinforcing effects. Treatment with a cross-tolerant
stimulant has been evaluated in a small number of clinical trials, with mixed
results. Alteration of cocaine pharmacokinetics has shown promise in animal
studies and early phase II clinical trials (9).
Cocaine has two major neuropharmacological actions: blockade of synaptic
neurotransmitter reuptake pumps, resulting in psychomotor stimulant effects and
blockade of sodium ion channels in nerve membranes, resulting in local
anesthetic effects.
Cocaine’s positively reinforcing effects derive from its blockade of the
dopamine reuptake pump, causing presynaptically released dopamine to remain
in the synapse and enhancing dopaminergic neurotransmission (10). Cocaine’s
local anesthetic effects are believed to contribute to cocaine-induced kindling,
the phenomenon by which previous exposure to cocaine sensitizes the individual
so that later exposure to low doses produces an enhanced response.
CHOICE OF MEDICATION
Antidepressants
A systematic review and meta-analysis of 28 published clinical trials (mean trial
duration 10.7 weeks) involving 2547 participants found that antidepressants as a
class (including tricyclics, selective serotonin reuptake inhibitors (SSRIs),
serotonin–norepinephrine uptake inhibitors, and the monoamine oxidase (MAO)
inhibitor selegiline) were no more effective than placebo in terms of drop-out
from treatment (relative risk 1.03, 95% CI 0.92-1.16) or number of weeks of
continuous abstinence (eight studies, 942 participants, mean difference 0.08,
95% CI −0.17-0.32) (11). However, there was some variation in efficacy across
types of antidepressants.
Tricyclic Antidepressants
Tricyclic antidepressants are the most widely used and best-studied class of
medications for the treatment of cocaine use disorder. Their pharmacological
mechanism of action is to increase biogenic amine neurotransmitter activity in
synapses, primarily by inhibiting presynaptic neurotransmitter reuptake pumps.
A systematic review and meta-analysis of 18 published clinical trials (17 with
desipramine, 1 with imipramine) at antidepressant doses involving 1293
participants found no advantage over placebo for drop-out rate (15 studies
involving 1141 participants, relative risk 1.00, 95% CI 0.85-1.18),but a
significant advantage in proportion of participants achieving at least 3 weeks of
continuous abstinence (5 studies involving 367 participants, relative risk 1.55,
95% CI 1.10-2.17) (11). This advantage over placebo disappeared when the
analysis was limited to the three studies that involved participants with
moderate-to-severe cocaine use disorder (234 participants, relative risk 1.41,
95% CI 0.93-2.14), suggesting that the therapeutic effect is not very robust.
Differences in patient characteristics, concomitant treatment, and
desipramine plasma concentrations may account for some of the variability in
the efficacy of desipramine. For example, patients with depression (12) and
without antisocial personality disorder (13) may respond best to desipramine.
Patients with cooccurring cocaine and opioid use disorders may do better on
desipramine if their opioid use is treated with buprenorphine rather than
methadone or if they receive contingency management treatment along with
medication (14). There is weak evidence that patients with steady-state
desipramine plasma concentrations above 200 ng/mL have poorer outcomes
(15), with better outcomes at concentrations around 125 ng/mL (14).
No unexpected or medically serious side effects have been reported in
published clinical trials of tricyclic antidepressants (11). However, patients who
relapse to cocaine use while still on antidepressant medications could, in theory,
be at increased risk of cardiovascular side effects. Both cocaine and the tricyclics
have quinidine-like membrane effects that, when superimposed, could lead to
cardiac arrhythmias. The concurrent administration of cocaine and desipramine
(blood levels above 100 ng/mL) to research volunteers has produced additive
increases in heart rate and blood pressure (16).

Antidepressants that selectively block the presynaptic serotonin reuptake pump
have attracted interest because of the role of serotonin and its receptors in
modulating dopaminergic brain reward circuits and the behavioral effects of
cocaine (17,18) (see Chapter 12, Section 2). A systematic review and meta-
analysis of eight published clinical trials (five with fluoxetine, one each with
citalopram, paroxetine, and sertraline) involving 662 participants found no
significant advantage over placebo in drop-out rate (6 studies involving 527
participants, relative risk 0.99, 95% CI 0.70-1.41) or craving for cocaine (3
studies involving 93 participants, standardized mean difference −0,22, 95% CI
−0.52-0.54) (11).
Serotonin–Norepinephrine Reuptake Inhibitors

Nefazodone (19,20) and venlafaxine (21), which block both serotonin and
norepinephrine reuptake, were not effective in controlled clinical trials.
Mirtazapine, which increases brain serotonin and norepinephrine activity by
blocking autoregulatory α2-adrenergic and 5-HT2 receptors, showed some
benefit in a small open-label trial (22).
Monoamine Oxidase Inhibitors
The rationale for use of MAO inhibitors lies in their effect of increasing brain
levels of biogenic amine neurotransmitters by inhibiting a major catabolic
enzyme. Limited open-label experience with phenelzine, at antidepressant doses
of 30-90 mg/d, suggests that this medication can reduce cocaine and other
stimulant use (23–25). However, its clinical usefulness may be limited by the
need for dietary and concomitant medication restrictions to avoid precipitating a
hypertensive crisis, as well as by the theoretical possibility of potentiating
cocaine-induced cardiovascular toxicity should the patient relapse to cocaine use
while still taking the medication. Some researchers have argued that fear of such
an aversive, potentially life-threatening reaction is what motivates abstinence
while taking an MAO inhibitor (23), making the mechanism of action analogous
to that of disulfiram for alcohol use disorder.
Selective MAO inhibitors that act only on MAO type B, the predominant
type in the brain, while sparing MAO type A, the predominant type in the
gastrointestinal tract, might obviate this issue. It is inhibition of MAO in the
gastrointestinal tract that produces a hypertensive crisis (“cheese reaction”) after
ingestion of tyramine-containing foods or certain catecholaminergic
medications. Selegiline, marketed for the treatment of parkinsonism and, in the
transdermal form, for treatment of depression, is fairly selective for MAO type B
at recommended doses (10 mg/d or 12 mg/d). A multisite, controlled clinical trial
using selegiline administered via a skin patch found no evidence for efficacy in
treatment of DSM-IV cocaine dependence (26).
Other Antidepressants
The norepinephrine reuptake inhibitors reboxetine (27) and maprotiline (28)
were effective in small open-label trials, while atomoxetine showed no efficacy
in a small controlled clinical trial (29).
Bupropion has attracted interest because it is a weak inhibitor of monoamine
reuptake and has some stimulant-like behavioral effects in animals. A meta-
analysis of two published controlled clinical trials involving 176 participants
found bupropion significantly better than placebo in promoting at least 3 weeks
of sustained abstinence in individuals with DSM-IV cocaine dependence (risk
ratio 1.63, 95% CI 1.03, 2.59) (30).
Dopamine Agonists (Antiparkinson Agents)

A variety of direct and indirect dopamine agonist medications have been
evaluated, based on the dopamine depletion hypothesis of cocaine addiction.
Dopamine agonists, by stimulating synaptic dopamine activity, would ameliorate
the effects of decreased dopamine activity caused by cessation of cocaine use;
these include anhedonia, anergia, depression, and cocaine craving.
A systematic review and meta-analysis of 24 published clinical trials
involving 2147 participants that evaluated direct dopamine receptor agonists
(bromocriptine, pergolide, pramipexole, cabergoline, hydergine), the indirect
dopamine agonist amantadine, and the amino acid dopamine precursor L-dopa
(sometimes combined with the peripheral dopa-decarboxylase inhibitor
carbidopa) together as a class found no evidence of efficacy compared to
placebo (31). An open-label trial of ropinirole in 39 patients with DSM-IV
cocaine dependence found it well tolerated and showed a significant reduction in
cocaine-positive urine specimens between baseline and week 6 of treatment (32).
L-Tyrosine, the amino acid precursor of L-dopa, reduced cocaine craving in a
small (12 patients) double-blind study of inpatients (33) but was not effective in
reducing cocaine use in two outpatient clinical trials at 2 g every 8 hours (open
label) (34) or 800 or 1600 mg twice a day (double blind) (35).
Disulfiram
Disulfiram can be considered a functional dopamine agonist because it blocks
the conversion of dopamine to norepinephrine by the enzyme dopamine-β-
hydroxylase, thereby increasing dopamine concentration (36). A systematic
review of seven published clinical trials involving 492 participants identified
several trials in which disulfiram (250 mg daily) was significantly better than
placebo in reducing drop-out rate or cocaine use (37). The trials could not be
combined for meta-analysis because of high heterogeneity and differences in
outcome measures. Only one (38) of five recent, larger controlled clinical trials
(39–42) found significant efficacy for disulfiram compared to placebo.
Some of the heterogeneity in treatment response to disulfiram may be due to
genetic factors. The recent positive clinical trial found no significant efficacy for
disulfiram in the subgroup of patients with a dopamine-β-hydroxylase gene
allele that results in low enzyme activity (38). Two other recent small controlled
clinical trials in patients receiving methadone that found no disulfiram efficacy
overall did find significant efficacy in subgroups with functional variants in the
ankyrin repeat and kinase domain-containing 1 (ANKK1) and dopamine D2
receptor (DRD2) genes (43) and α1A-adrenoreceptor (ADRA1A) gene (44).
Gender may also influence the treatment response to disulfiram. A review of
five published controlled clinical trials involving 434 participants found that
disulfiram was less effective in reducing cocaine use in women than in men (45).
There was no such gender difference in response to behavioral treatments.
Although disulfiram is well tolerated in clinical trials, where subjects are
carefully screened for medical and psychiatric comorbidity, questions have been
raised about its safety in routine clinical practice (46). Several human laboratory
studies give conflicting results on the safety of the cocaine–disulfiram
interaction (47), although one study found no clinically significant adverse
effects from even the triple interaction of cocaine–alcohol–disulfiram (48).
These findings suggest that disulfiram may be a promising treatment for cocaine
use disorder in some subgroups of patients, although raising a caution about
potential adverse drug interactions should patients use cocaine while on the
medication. However, preliminary findings from a recently completed 12-week,
controlled clinical trial with nepicastat, a dopamine beta-hydroxylase inhibitor
that does not have significant pharmacological interactions with cocaine (49),
suggest that the medication has no significant benefit in reducing cocaine use
(www.clinicaltrials.gov, trial number NCT01704196, accessed 06/18/2018) .
Serotonergic Agents
Buspirone and gepirone are primarily 5-HT1A receptor agonists used to treat
generalized anxiety disorder. Controlled clinical trials found neither effective in
reducing cocaine use (50,51).
Ritanserin, a 5-HT2 receptor antagonist developed as an antidepressant, was
no better than placebo in reducing cocaine use in two controlled clinical trials
(52,53).
Ondansetron, a 5-HT3 receptor antagonist approved for the treatment of
nausea and vomiting, significantly reduced cocaine use in a small controlled
clinical trial, but only at the highest dose (4 mg twice daily) (54).
Cholinergic Agents
Muscarinic cholinergic agents influence cocaine reward in animal models, both
directly and by modulating dopaminergic neurotransmission (55). Biperiden (2
mg tid), a muscarinic cholinergic receptor antagonist used to treat movement
disorders, significantly reduced cocaine use in a small controlled clinical trial
(55). Mecamylamine, a nicotinic cholinergic receptor antagonist, did not reduce
cocaine use in a small controlled clinical trial (56).
Varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors
approved for smoking cessation, significantly reduced cocaine use in a small
controlled clinical trial (57). Increasing brain cholinergic activity nonspecifically
by inhibiting acetylcholinesterase activity with donepezil (58) or galantamine
(59) had no effect on cocaine use in small controlled clinical trials.
Opioid Receptor Ligands

μ-Opioid receptor (mOR) antagonists have been evaluated as treatments for
cocaine use disorder because of the role of brain mORs in cocaine use. Those
who use cocaine on a chronic basis have a decreased response to mOR agonists
compared to those who do not use cocaine (60), and elevated mOR binding
potential in brain regions associated with reward sensitivity is associated with
increased cocaine craving (61), increased rate of relapse after enforced
abstinence (62), and greater cocaine use during outpatient treatment (63). These
findings suggest that blockade of μ-opioid receptors might reduce cocaine
craving and use. Three small controlled clinical trials (two placebo-controlled)
found that naltrexone (50 mg daily) significantly reduced cocaine use compared
to placebo (64,65) or to cognitive–behavioral therapy without medication (66).
Buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor
antagonist approved for the treatment of opioid use disorder, has been studied for
the treatment of cocaine use disorder, in part because of its efficacy in treating
patients with concurrent cocaine and opioid use disorders (see Concurrent
Opioid Use Disorder below). A controlled clinical trial with buprenorphine (4
mg or 16 mg daily sublingually for 8 weeks) in 302 participants with current
DSM-IV cocaine dependence and past or current opioid abuse or dependence
found no significant group differences in treatment retention or cocaine use (by
self-report and urine drug testing) (67). However, a longitudinal analysis of urine
drug testing data within treatment groups found, compared to placebo, a
significantly lower rate of cocaine-positive urine samples in the buprenorphine,
16 mg group (OR 1.71, p = 0.022), and no difference in the buprenorphine, 4 mg
group (OR 1.05, p = 0.105).
Stimulants
By analogy with methadone and buprenorphine treatment of opioid use disorder
or nicotine treatment of tobacco use disorder, treatment of patients with cocaine
use disorder with stimulant medication might be beneficial in reducing cocaine
craving and use. As with methadone and buprenorphine, advantages might
include use of the less medically risky oral route of administration (vs. injected
or smoked cocaine), use of pure medication of known potency (thus avoiding
adulterant effects or inadvertent overdose), provision by a medical professional
as part of a comprehensive treatment regimen, and use of a medication with
slower onset (less euphoria) and longer duration (eg, daily dosing) of action
(thus avoiding “rush”/“crash” cycling).
involving 1549 participants found that stimulants as a class (including
dexamphetamine, mixed amphetamine salts, methamphetamine,
lisdexamfetamine, methylphenidate, modafinil, and mazindol) were significantly
better than placebo in promoting at least 3 weeks of sustained abstinence (risk
ratio 1.36, 95% CI 1.05-1.77), but did not increase proportion of cocaine-free
urine samples among those who did not achieve sustained abstinence (8 studies
involving 516 participants, standardized mean difference 0.16, 95% CI −0.02-
0.33) nor improve study retention (12 studies involving 2205 participants, risk
ratio 1.00, 95% CI 0.93-1.06) (30). Among specific stimulants, only
dexamphetamine (3 studies involving 154 participants, risk ratio 1.98, 95% CI
1.12-3.52) and mixed amphetamine salts (1 study involving 176 participants,
risk ratio 3.63, 95% CI 1.15-11.48) were significantly better than placebo in
promoting at least 3 weeks of sustained abstinence.
A recent controlled clinical trial involving 73 participants with cocaine use
disorder who were receiving heroin treatment for opioid use disorder confirmed
the efficacy of sustained release dexamphetamine, which was associated with a
mean difference of 16.7 (95% CI 3.1-28.4) fewer days of cocaine use, compared
to placebo, over the 12-week trial (68).
In principle, cocaine itself, in a slow-onset formulation or route of
administration, might be used for agonist treatment (69,70), in the same way that
slow-onset transdermal or transbuccal nicotine is used to treat addiction to rapid-
onset smoked nicotine (cigarettes). Oral cocaine salt capsules (100 mg four times
a day) significantly attenuated the response to an intravenous cocaine challenge
(25 mg) (70) and reduced coca paste smoking in an open-label series of 18
patients in Lima, Peru (where oral cocaine products are legal) (71). A larger
series of 200 patients treated with coca tea, also in Lima, reported that almost
80% reduced their cocaine smoking (71). A case series of 50 individuals who
smoked coca paste in La Paz, Bolivia, reported that chewing 100-200 g of coca
leaf per week for a mean of 2 years substantially improved the mental health of
one-third of the patients and improved the socioeconomic functioning of almost
half (data on cocaine smoking were not reported) (72).
Antipsychotics
The older (so-called first-generation or “typical”) antipsychotics, which are
potent dopamine receptor antagonists (chiefly D2 [postsynaptic] subtype), do not
significantly alter cocaine craving or use, as evidenced by clinical experience
with patients with schizophrenia who use cocaine while receiving chronic
antipsychotic treatment (73–75). Greater effectiveness was expected from the
newer “second-generation” (so-called “atypical”) antipsychotics, in part because
of their broader spectrum of receptor binding (including dopamine D1 and
serotonin receptors). However, a systematic review and meta-analysis of 14
published clinical trials involving 719 participants found that anti-psychotics as a
class (aripiprazole, olanzapine, quetiapine, risperidone, and one study each with
haloperidol or reserpine) reduced study dropout (8 studies involving 397
participants, risk ratio 0.75, 95% CI 0.57-0.97) but did not significantly reduce
proportion of subjects achieving at least 3 weeks of continuous abstinence (3
studies involving 139 participants, risk ratio 1.30, 95% CI 0.73-2.32) or number
of participants using cocaine during treatment (2 studies involving 91
participants, risk ratio 1.02, 95% CI 0.65-1.62) (76). A recent controlled clinical
trial of aripiprazole in individuals who use cocaine who had achieved 2 weeks of
continuous abstinence with contingency management found no significant
reduction in lapse or relapse rates but a significant increase in cocaine craving
(77).
Caution should be exercised when prescribing any antipsychotic medication
to those who use cocaine because of their potential vulnerability to the
neuroleptic malignant syndrome, based on their presumed cocaine-induced
dopamine depletion (78). Individuals who use cocaine or amphetamine may also
be at elevated risk of antipsychotic-induced movement disorders (79–82).
Anticonvulsants
Anticonvulsants might be effective in the treatment of cocaine use disorder
because they increase inhibitory GABA activity and/or decrease excitatory
glutamate activity in the brain, both actions that would decrease the response to
cocaine in the dopaminergic cortico-mesolimbic brain reward circuit (83–85).
involving 2068 participants found that anticonvulsants as a class
(carbamazepine, gabapentin, lamotrigine, phenytoin, tiagabine, topiramate, and
vigabatrin) had no significant effect on drop-out rate (17 studies involving 1695
participants, risk ratio 0.95, 95% CI 0.86-1.05), cocaine use (9 studies involving
867 participants, risk ratio 0.92, 95% CI 0.84-1.02), or cocaine craving (7 studies
involving 428 participants, standardized mean difference −0.25, 95% CI −0.59-
0.09) (86). When considered individually, no anticonvulsant showed any
significant benefit over placebo. However, a separate meta-analysis including
only the two topiramate trials (including 210 participants) that evaluated
proportion of subjects maintaining continuous abstinence for at least 3 weeks
found a si

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Richard N. Rosenthal, MA, MD, DFAPA, DFAAAP,

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